Drug delivery devices for delivery of ocular therapeutic agents

ABSTRACT

Drug delivery devices comprising a non-bioabsorbable polymer structure configured to support a composition comprising an active agent. The devices include a plurality of portions fused together and a recess configured to support the composition. At least one of the portions includes an impermeable polymer and at least one other portion includes a rate-limiting water-permeable polymer. The rate-limiting water-permeable polymer allows for transportation of the active agent to an exterior of the device.

RELATED APPLICATIONS

This application in a non-provisional application of and claims priorityto provisional patent application No. 61/345,547, filed on May 17, 2010,the entire contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a drug delivery device for sustaineddelivery of therapeutic agents to target tissues. In particular, itrelates to a non-biodegradable, drug-eluting removable device for thepurpose of treating various diseases and conditions. More particularly,but not by way of limitation, this device is well-suited for episcleralor supraconjunctival delivery of pharmaceutical agents for the treatmentof glaucoma and ocular hypertension.

BACKGROUND OF THE INVENTION

The delivery of therapeutic and pharmaceutical agents is a complexproblem without a single universal solution. Many chronic diseases andconditions can be treated effectively by oral medications, but sideeffects, patient forgetfulness, and other factors often produce highrates of noncompliance with the recommended treatment. In such cases,patient outcomes can be improved using sustained delivery formulationsthat simplify the medication regimen (e.g., Lupron Depot® forendometriosis).

Where possible, diseases and conditions that affect only a single organor local tissue are preferably treated by a local application. Thisallows for a relatively high concentration of the therapeutic agent atthe site where it is most needed, and allows for minimal systemicexposure. However there are relatively few tissues that are directlyaccessible, with skin, hair follicles, the oral, nasal and genitourinarycavities, and eyes being candidates for direct application oftherapeutic agents. Direct application of therapeutic agents to internalorgans is more challenging, but has been useful in the treatment of sometypes of tumors.

In the treatment of ocular conditions in particular, many medicationsare now delivered topically to the eye as eyedrops. Despite the successof the eyedrop in treating diseases and conditions of the eye, treatmentwith topical eyedrops suffers from numerous drawbacks.

A significant drawback of the eyedrop is the requirement that thepharmaceutical agent be soluble in an isotonic buffered solution at atherapeutically effective concentration and be chemically stable insolution for 18 months or longer. However, solubility of usefultherapeutic agents in aqueous formulation is often well below theconcentration needed for effective treatment. This can sometimes becorrected by the addition of various excipients, but this increases thecomplexity of the formulation and often reduces tolerability of theeyedrop.

A second limitation of eyedrops is the rapid clearance of thetherapeutic agent via nasolacrimal drainage from the eye surface. Thisresults in most of the compound being delivered to the inside of thenose, where it is not needed and where, in fact, a high concentration ofagent might have a detrimental effect.

A third limitation to the use of eyedrops is the observation that manytherapeutically-valuable agents cause a local irritation whentopically-dosed to the eye. The cornea of the eye is highly sensitive tothe application of chemical agents. This irritation potentialsignificantly limits the use of many otherwise valuable therapeuticagents.

A fourth limitation of eyedrops, which also applies to systemic drugstaken by oral, sublingual, nasal or rectal delivery routes, is the needto re-apply the therapeutic agent on a regular basis. For eyedrops,repeating application as frequently as four times a day can benecessary, and even the best agents must be reapplied on a daily basis.For many individuals, in particular the elderly, this frequent dosingbecomes burdensome and leads to non-compliance with the dosing regimen,lessening the therapeutic value of the treatment.

To counter these disadvantages of eyedrop delivery, researchers havesuggested various devices aimed at providing local delivery over alonger period of time. U.S. Pat. No. 5,824,072 to Wong discloses anon-biodegradable implant containing a pharmaceutical agent thatdiffuses through a water-impermeable polymer matrix into the targettissue. The implant is placed in the tear film or in asurgically-induced avascular region, or in direct communication with thevitreous.

U.S. Pat. No. 5,476,511 to Gwon et al. discloses a polymer implant forplacement under the conjunctiva of the eye. The implant is claimed to beuseful for the delivery of neovascular inhibitors for the treatment ofage-related macular degeneration (AMD). Again, the pharmaceutical agentdiffuses through a water-impermeable polymer matrix of the implant.

U.S. Pat. No. 5,773,019 to Aston et al. discloses a non-biodegradableimplant for the delivery of steroids and immunosuppressives such ascyclosporine for the treatment of uveitis, with the drug again diffusingthrough the water-impermeable polymer matrix of the implant.

U.S. Pat. No. 3,854,480 to Zaffaroni discloses a drug-delivery systemwith a solid inner matrix formulation containing solid particles of drugsurrounded by an outer polymer membrane that is permeable to the passageof the drug. While both the inner matrix and the outer wall are claimedto be permeable to the passage of drugs, the patent requires that therate of diffusion of the outer membrane be not more than 10% of the rateof the inner matrix.

Both U.S. Pat. No. 4,281,654 to Shell, et al. and U.S. Pat. No.4,190,642 to Gale, et al. disclose matrix polymer systems that aredesigned to deliver either beta-blockers or a combination of epinephrineand pilocarpine to the eye to treat glaucoma. Gale, et al. micronizetheir medicaments to a particle size of not more than 100 microns andthese are subsequently dispersed throughout the entire polymer matrix,with no distinct cavity that contains the drug and no drug-free outerlayer. In addition, both Shell and Gale require the walls surroundingthese small depots be ruptured by the force of the osmotic pressure inorder to release the drug by way of those formed ruptures.

All of the above-referenced patents and publications are herebyincorporated herein by reference.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides an implantable devicecomprising a first portion including a recess configured to support acomposition comprising an active agent, the first portion comprising animpermeable polymer and a second portion fused to the first portion, thesecond portion comprising a rate-limiting water-permeable polymer thatallows for transportation of the active agent to an exterior of thedevice.

In one embodiment, the present invention includes a device for insert inthe eye. The device comprises a first portion including a recessconfigured to support a composition comprising an active agent, thefirst portion comprising an impermeable polymer; and a second portionfused to the first portion, the second portion comprising arate-limiting water-permeable polymer that allows for transportation ofthe active agent to an exterior of the device.

In another embodiment, the present invention includes a device forinsert in the eye. The device comprises a first portion including arecess configured to support a composition comprising an active agent,the first portion comprising an impermeable polymer; a second portionfused to the first portion, the second portion comprising arate-limiting water-permeable polymer that allows for transportation ofthe active agent to an exterior of the device; and a flange fused to thesecond portion.

In a further embodiment, the present invention includes a device forinsert in the eye. The device comprises a first portion including arecess configured to support a composition comprising an active agent,the first portion comprising an impermeable polymer; and a secondportion fused to the first portion, the second portion including a baseand a flange integral with the base, the second portion comprising arate-limiting water-permeable polymer that allows for transportation ofthe active agent to an exterior of the device.

In yet another embodiment, the present invention includes a device forinsert in the eye. The device comprises a first portion comprising arate-limiting water-permeable polymer; a second portion fused to thefirst portion, the second portion including a recess configured tosupport a composition comprising an active agent, the second portioncomprising a rate-limiting water-permeable polymer; and a third portionfused to the second portion, the third portion comprising arate-limiting water-permeable polymer. The rate-limiting water-permeablepolymer allows for transportation of the active agent to an exterior ofthe device.

In another embodiment, the present invention includes a method oftreating an ocular condition comprising suturing an embodiment of one ofthe devices disclosed herein to the conjunctiva of the eye.

In a further embodiment, the present invention includes a method oftreating an ocular condition comprising implanting episclerally orsupraconjunctivally a drug delivery device comprising an active agent,wherein the active agent is released at a rate of about 0.0001 to about200 micrograms/hr.

Other aspects of the invention will become apparent by consideration ofthe detailed description and accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a drug delivery device according to one embodiment of thepresent invention.

FIG. 2 shows a drug delivery device according to one embodiment of thepresent invention.

FIG. 3 illustrates a cross-sectional view of the eye with a drugdelivery device according to one embodiment of the present inventioninserted in the eye.

FIG. 4 illustrates several drawings of a drug delivery device accordingto one embodiment of the present invention.

FIG. 5 is an exploded view of the drug delivery device illustrated inFIG. 4.

FIG. 6 illustrates several drawings of a composition supported by thedrug delivery device illustrated in FIG. 4.

FIG. 7 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 4.

FIG. 8 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 4.

FIG. 9 illustrates several drawings of a drug delivery device accordingto one embodiment of the present invention.

FIG. 10 is an exploded view of the drug delivery device illustrated inFIG. 9.

FIG. 11 illustrates several drawings of a composition supported by thedrug delivery device illustrated in FIG. 9.

FIG. 12 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 9.

FIG. 13 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 9.

FIG. 14 illustrates several drawings of a drug delivery device accordingto one embodiment of the present invention.

FIG. 15 is an exploded view of the drug delivery device illustrated inFIG. 14.

FIG. 16 illustrates several drawings of a composition supported by thedrug delivery device illustrated in FIG. 14.

FIG. 17 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 14.

FIG. 18 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 14.

FIG. 19 illustrates several drawings of a drug delivery device accordingto one embodiment of the present invention.

FIG. 20 is an exploded view of the drug delivery device illustrated inFIG. 19.

FIG. 21 illustrates several drawings of a composition supported by thedrug delivery device illustrated in FIG. 19.

FIG. 22 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 19.

FIG. 23 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 19.

FIG. 24 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 19.

FIG. 25 illustrates several drawings of a drug delivery device accordingto one embodiment of the present invention.

FIG. 26 is an exploded view of the drug delivery device illustrated inFIG. 25.

FIG. 27 illustrates several drawings of a composition supported by thedrug delivery device illustrated in FIG. 25.

FIG. 28 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 25.

FIG. 29 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 25.

FIG. 30 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 25.

FIG. 31 illustrates several drawings of a drug delivery device accordingto one embodiment of the present invention.

FIG. 32 is an exploded view of the drug delivery device illustrated inFIG. 31.

FIG. 33 illustrates several drawings of a composition supported by thedrug delivery device illustrated in FIG. 31.

FIG. 34 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 31.

FIG. 35 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 31.

FIG. 36 illustrates several drawings of a drug delivery device accordingto one embodiment of the present invention.

FIG. 37 is an exploded view of the drug delivery device illustrated inFIG. 36.

FIG. 38 illustrates several drawings of a composition supported by thedrug delivery device illustrated in FIG. 36.

FIG. 39 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 36.

FIG. 40 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 36.

FIG. 41 illustrates several drawings of a drug delivery device accordingto one embodiment of the present invention.

FIG. 42 is an exploded view of the drug delivery device illustrated inFIG. 41.

FIG. 43 illustrates several drawings of a composition supported by thedrug delivery device illustrated in FIG. 41.

FIG. 44 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 41.

FIG. 45 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 41.

FIG. 46 illustrates several drawings of a drug delivery device accordingto one embodiment of the present invention.

FIG. 47 is an exploded view of the drug delivery device illustrated inFIG. 46.

FIG. 48 illustrates several drawings of a composition supported by thedrug delivery device illustrated in FIG. 46.

FIG. 49 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 46.

FIG. 50 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 45.

FIG. 51 illustrates several drawings of a drug delivery device accordingto one embodiment of the present invention.

FIG. 52 is an exploded view of the drug delivery device illustrated inFIG. 51.

FIG. 53 illustrates several drawings of a composition supported by thedrug delivery device illustrated in FIG. 51.

FIG. 54 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 51.

FIG. 55 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 51.

FIG. 56 illustrates several drawings of a drug delivery device accordingto one embodiment of the present invention.

FIG. 57 is an exploded view of the drug delivery device illustrated inFIG. 56.

FIG. 58 illustrates several drawings of a composition supported by thedrug delivery device illustrated in FIG. 56.

FIG. 59 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 56.

FIG. 60 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 56.

FIG. 61 illustrates several drawings of a drug delivery device accordingto one embodiment of the present invention.

FIG. 62 is an exploded view of the drug delivery device illustrated inFIG. 61.

FIG. 63 illustrates several drawings of a composition supported by thedrug delivery device illustrated in FIG. 61.

FIG. 64 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 61.

FIG. 65 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 61.

FIG. 66 illustrates several drawings of a drug delivery device accordingto one embodiment of the present invention.

FIG. 67 is an exploded view of the drug delivery device illustrated inFIG. 66.

FIG. 68 illustrates several drawings of a composition supported by thedrug delivery device illustrated in FIG. 66.

FIG. 69 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 66.

FIG. 70 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 66.

FIG. 71 illustrates several drawings of a drug delivery device accordingto one embodiment of the present invention.

FIG. 72 is an exploded view of the drug delivery device illustrated inFIG. 71.

FIG. 73 illustrates several drawings of a composition supported by thedrug delivery device illustrated in FIG. 71.

FIG. 74 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 71.

FIG. 75 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 71.

FIG. 76 illustrates several drawings of a drug delivery device accordingto one embodiment of the present invention.

FIG. 77 is an exploded view of the drug delivery device illustrated inFIG. 76.

FIG. 78 illustrates several drawings of a composition supported by thedrug delivery device illustrated in FIG. 76.

FIG. 79 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 76.

FIG. 80 illustrates several drawings of a portion of the drug deliverydevice illustrated in FIG. 76.

FIG. 81 shows the release profile for a drug delivery device accordingto the present invention.

FIG. 82 shows the release profile for a drug delivery device accordingto the present invention.

FIG. 83 shows the IOP-lowering effect of a drug delivery deviceaccording to the present invention.

FIG. 84 shows the release profile of a drug delivery device according tothe present invention.

FIG. 85 shows the IOP-lowering effect of a drug delivery deviceaccording to the present invention.

FIG. 86 shows the release profile of a drug delivery device according tothe present invention.

FIG. 87 shows the IOP-lowering effect of a drug delivery deviceaccording to the present invention.

FIG. 88 shows the release profile of a drug delivery device according tothe present invention.

FIG. 89 shows the release profile of a drug delivery device according tothe present invention.

FIG. 90 shows the release profile of a drug delivery device according tothe present invention.

FIG. 91 shows the IOP-lowering effect of a drug delivery deviceaccording to the present invention.

FIG. 92 shows the release profile of a drug delivery device according tothe present invention.

FIG. 93 shows the release profile of a drug delivery device according tothe present invention.

FIG. 94 shows the IOP-lowering effect of a drug delivery deviceaccording to the present invention.

FIG. 95 shows a flowchart for designing drug delivery devices.

FIG. 96 shows a flowchart for designing drug delivery devices.

FIG. 97 shows solubility characteristics for various active agents.

DETAILED DESCRIPTION

Before any embodiments of the invention are explained in detail, it isto be understood that the invention is not limited in its application tothe details of construction and the arrangement of components set forthin the following description or illustrated in the following drawings.The invention is capable of other embodiments and of being practiced orof being carried out in various ways. Also, it is to be understood thatthe phraseology and terminology used herein is for the purpose ofdescription and should not be regarded as limiting. The use of“including,” “comprising,” or “having” and variations thereof herein ismeant to encompass the items listed thereafter and equivalents thereofas well as additional items. Unless specified or limited otherwise, theterms “mounted,” “connected,” “supported,” and “coupled” and variationsthereof are used broadly and encompass both direct and indirectmountings, connections, supports, and couplings.

Although directional references, such as upper, lower, downward, upward,rearward, bottom, front, rear, etc., may be made herein in describingthe drawings, these references are made relative to the drawings (asnormally viewed) for convenience. These directions are not intended tobe taken literally or limit the present invention in any form. Inaddition, terms such as “first,” “second,” and “third” are used hereinfor purposes of description and are not intended to indicate or implyrelative importance or significance.

FIG. 1 illustrates a drug delivery device 10 according to one embodimentof the present invention. The drug delivery device 10 comprises anon-bioabsorbable polymer structure 14 which encloses a composition 18comprising an active agent. The active agent is released through thepolymer structure once the drug delivery device is implanted in thedesired portion of the body.

The non-bioabsorbable polymer structure 14 comprises, in one embodimentshown in FIG. 1, a mixture comprising a water-soluble polymer and anon-water soluble polymer with about 0% to about 50% by weight of themixture being the water-soluble polymer or about 10% to about 30% byweight. Suitably, the drug delivery device 10 at least partiallybioerodes when implanted in the body as the water-soluble polymerdissolves leaving a porous non-bioabsorbable polymer structure throughwhich the active agent is released. The polymer structure 14 suitablyhas a thickness of about 20 micrometers to about 800 micrometers orabout 40 micrometers to about 500 micrometers or about 50 micrometers toabout 250 micrometers, depending on the overall size and requiredmechanical strength of the device 10.

The non-water soluble polymer may be selected from ethylene vinylacetate (EVA), silicon rubber polymers, polydimethylsiloxane (PDMS),polyurethane (PU), polyesterurethanes, polyetherurethanes, polyolefins,polyethylenes (PE), low density polyethylene (LDPE), polypropylene (PP),polyetheretherketone (PEEK), polysulfone (PSF), polyphenylsulfone,polyacetals, polymethyl methacrylate (PMMA), polybutylmethacrylate,plasticized polyethyleneterephthalate, polyisoprene, polyisobutylene,silicon-carbon copolymers, natural rubber, plasticized soft nylon,polytetrafluoroethylene (PTFE), or combinations thereof. Suitably, thenon-water soluble polymer is EVA. The vinyl acetate content may be fromabout 9% to about 50% by weight (EVA-9-50). In one embodiment, the vinylacetate content is about 40% by weight (EVA-40). Other suitablenon-water soluble polymers are known to those of ordinary skill in theart.

The water-soluble polymer may be selected from dextran, cyclodextrin,poly-(L-lactic acid), polycaprolactone, poly(lactic-co-glycolic acid),poly(glycolic acid), poly(trimethylene carbonate), polydioxanone orcombinations thereof. Other suitable water-soluble polymers are known tothose of ordinary skill in the art.

Alternatively, in an embodiment shown in FIG. 2, the non-bioabsorbablepolymer structure 14 comprises an impermeable polymer 22 and apartially-bioerodible membrane 26. Suitably, about 0% to about 50% byweight of the polymer structure 14 is the partially-bioerodible membrane26 or about 10% to about 30% by weight of the partially-bioerodiblemembrane 26. The impermeable polymer 22 does not allow the passage ofthe active agent and provides mechanical strength for the device 10. Theimpermeable polymer 22 suitably has a thickness of about 50 micrometersto about 800 micrometers or about 100 micrometers to about 250micrometers, depending on the overall size and required mechanicalstrength of the device 10. The partially-bioerodible membrane 26suitably has a thickness of about 20 micrometers to about 800micrometers or about 40 micrometers to about 500 micrometers, dependingon the overall size and required mechanical strength of the device 10.

Suitable impermeable polymers 22 include, but are not limited to,EVA-9-50, silicon rubber polymers, polydimethylsiloxane (PDMS),polyurethane (PU), polyesterurethanes, polyetherurethanes, polyolefins,polyethylenes (PE), low density polyethylene (LDPE), polypropylene (PP),polyetheretherketone (PEEK), polysulfone (PSF), polyphenylsulfone,polyacetals, polymethyl methacrylate (PMMA), polybutylmethacrylate,plasticized polyethyleneterephthalate, polyisoprene, polyisobutylene,silicon-carbon copolymers, natural rubber, plasticized soft nylon,polytetrafluoroethylene (PTFE), or combinations thereof. Other suitableimpermeable polymers 22 are known to those of ordinary skill in the art.

In some embodiments, the partially-bioerodible membrane 26 comprises animpermeable polymer and a bioerodible polymer. Suitably, thepartially-bioerodible membrane 26 contains about 0% to about 50% byweight of the bioerodible polymer. Suitable bioerodible polymersinclude, but are not limited to, dextran, cyclodextrin, poly-(L-lacticacid), polycaprolactone, poly(lactic-co-glycolic acid), poly(glycolicacid), poly(trimethylene carbonate), polydioxanone, or combinationsthereof. Other suitable bioerodible polymers are known to those ofordinary skill in the art.

In another embodiment also encompassed by FIG. 2, the non-bioabsorbablepolymer structure 14 comprises an impermeable polymer 22 and arate-limiting water-permeable polymer 30. Suitably, the polymerstructure contains about 0% to about 50% by weight of the rate-limitingwater-permeable polymer or about 10% to about 30% by weight of therate-limiting water-permeable polymer. The impermeable polymer 22 doesnot allow the passage of the active agent and provides mechanicalstrength for the device 10. The impermeable polymer 22 suitably has athickness of about 50 micrometers to about 800 micrometers or about 100micrometers to about 250 micrometers, depending on the overall size andrequired mechanical strength of the device 10.

Suitable impermeable polymers 22 include, but are not limited to,EVA-9-50, silicon rubber polymers, polydimethylsiloxane (PDMS),polyurethane (PU), polyesterurethanes, polyetherurethanes, polyolefins,polyethylenes (PE), low density polyethylene (LDPE), polypropylene (PP),polyetheretherketone (PEEK), polysulfone (PSF), polyphenylsulfone,polyacetals, polymethyl methacrylate (PMMA), polybutylmethacrylate,plasticized polyethyleneterephthalate, polyisoprene, polyisobutylene,silicon-carbon copolymers, natural rubber, plasticized soft nylon,polytetrafluoroethylene (PTFE), or combinations thereof. Other suitableimpermeable polymers 22 are known to those of ordinary skill in the art.

The rate-limiting water-permeable polymer 30 is a polymer that allowsfor the passage of active agent and water or tissue fluids. Thecomposition and/or thickness of this polymer determines the rate ofrelease from the drug delivery device. The water-permeable polymer 30has limited water permeability which only allows water passage into thedrug core 18 at a very slow rate. Once water penetrates the polymer 30into the enclosed drug core 18, it then serves as a solvent to dissolvethe active agent to its solubility limit. Therefore, the active agentsuitably has low or moderate solubility. In one embodiment, the majorityof the active agent remains as a solid compressed form and theconcentration of the dissolved aqueous portion remains at its solubilitylimit, so that the concentration gradient across the polymer remainssubstantially constant, given that the clearance rate is sufficient inthe environment. Without wishing to be bound by theory, in oneembodiment the above described mechanisms allow this polymer to providethe rate-limiting steps that allow the active agent to be released at asubstantially constant rate until at least about 70% to at most about95% of the active agent is released from the drug delivery device. Therate-limiting water-permeable polymer 30 suitably has a thickness ofabout 20 micrometers to about 500 micrometers, depending on the overallsize and required mechanical strength of the device 10.

Suitable rate-limiting water-permeable polymers 30 may be selected fromethylene vinyl acetate with a vinyl acetate content of about 26% toabout 80% by weight (EVA-26-80) or ethylene vinyl alcohol with a vinylalcohol content of about 40% to about 80% by weight (EVOH-40-80).Suitable rate-limiting water-permeable polymers 30 may be copolymersthat have both hydrophobic and hydrophilic monomers where thehydrophilic portion allows the passage of water or tissue fluids and thehydrophobic portion limits its water-permeability in order to providethe rate-limiting barrier. Other suitable rate-limiting water-permeablepolymers are known to those of ordinary skill in the art.

In some embodiments, the drug delivery device 10 has a cylindricalstructure. Suitably, the cylindrical structure comprises a cylindricalwall, a top and a bottom. The top and the bottom are coupled to oppositesides of the cylindrical wall. In some embodiments, the cylindrical walland top comprise the impermeable polymer 22 and the bottom comprises thepartially-bioerodible membrane 26 or rate-limiting water-permeablepolymer 30. In other embodiments, drug delivery device 10 can bespherical, tubular, rod-shaped, or the like.

FIG. 3 illustrates one embodiment of a drug delivery device 10 insertedor implanted in the eye. For episcleral implantation, a small incision(˜3 mm) is made in the conjunctiva near the limbus in the superiortemporal episcleral zone of the eye, and a drug delivery device 10according to one embodiment of the present invention is introducedthrough the incision into the sub-Tenon's space. Closing theconjunctival incision by suture is optional. For supraconjunctivalplacement, a drug delivery device 10 according to one embodiment of thepresent invention is gently inserted into the upper or lower fornix ofthe eye. Depending on the size/shape and desired duration of use, thedrug delivery device 10 may be sutured to the conjunctiva to immobilizesuch device.

Although FIG. 3 illustrates one embodiment of a drug delivery device 10inserted in the eye, any one of the drug delivery devices disclosedherein can be inserted or implanted in the eye as described above.

FIGS. 4-8 illustrate a drug delivery device 34 according to anotherembodiment of the present invention. The drug delivery device 34 isgenerally cylindrical-shaped and includes a first portion 38 and asecond portion 42. The first portion 38 includes a bottom surface 46, atop surface 50, and an outer side surface 54 positioned between andextending around a periphery of the bottom surface 46 and the topsurface 50. The first portion 38 includes a recess 58 defined by aninner side wall 62 and a bottom surface 66. The bottom surface 66 ispositioned a predetermined distance from the bottom surface 46.

The recess 54 is configured to support the composition 18 comprising anactive agent (as discussed above). The dimensions of the recess 58 aresimilar to the dimensions of the composition 18 such that thecomposition 18 (in its undissolved state or pre-insertion state) cannotmove freely within the recess 58. The inner side wall 62 is generallyconcentric with the outer side surface 54 and is spaced from the outerside surface 54 around its entire circumference. The outer side surface54 includes a first diameter 70, and the inner side wall 62 includes asecond diameter 74. The first diameter 70 is generally greater than thesecond diameter 74.

The second portion 42 includes a bottom surface 78, a top surface 82,and a side surface 86 positioned between and extending around aperiphery of the bottom surface 78 and the top surface 82. The bottomsurface 78 of the second portion 42 interfaces with the top surface 50of the first portion 38 to enclose the composition 18 within the recess58.

The first portion 38 comprises an impermeable polymer 22 as discussedabove. The impermeable polymer 22 does not allow the passage of theactive agent and provides mechanical strength for the device 34. Theimpermeable polymer 22 suitably has a thickness of about 50 micrometersto about 800 micrometers or about 100 micrometers to about 250micrometers, depending on the overall size and required mechanicalstrength of the device 34.

The second portion 42 comprises a rate-limiting water-permeable polymer30 as discussed above. The rate-limiting water-permeable polymer 30 is apolymer that allows for the passage of the active agent and water ortissue fluids. The composition and/or thickness of this polymerdetermines the rate of release from the drug delivery device. Therate-limiting water-permeable polymer 30 suitably has a thickness ofabout 20 micrometers to about 500 micrometers, depending on the overallsize and required mechanical strength of the device 34.

FIGS. 9-13 illustrate a drug delivery device 90 according to anotherembodiment of the present invention. The drug delivery device 90 isgenerally cylindrical-shaped and includes a first portion 94 and asecond portion 98. The first portion 94 includes a bottom surface 102, atop surface 106, and an outer side surface 110 positioned between andextending around a periphery of the bottom surface 102 and the topsurface 106. The first portion 94 includes a recess 114 defined by aninner side wall 118 and a bottom surface 122. The bottom surface 122 ispositioned a predetermined distance from the bottom surface 102.

The recess 114 is configured to support the composition 18 comprising anactive agent (as discussed above). The recess 114 includes an axisextending between the bottom surface 122 and the top surface 106. Thedimensions of the recess 114 are similar to the dimensions of thecomposition 18, but extra space exists between the top surface 106 andthe composition 18 and/or between the bottom surface 122 and thecomposition 18, such that the composition 18 (in its undissolved stateor pre-insertion state) can move along the axis within the recess 114.The inner side wall 118 is generally concentric with the outer sidesurface 110 and is spaced from the outer side surface 110 around itsentire circumference. The outer side surface 110 includes a firstdiameter 126, and the inner side wall 118 includes a second diameter130. The first diameter 126 is generally greater than the seconddiameter 130.

The second portion 98 includes a bottom surface 134, a top surface 138,and a side surface 142 positioned between and extending around aperiphery of the bottom surface 134 and the top surface 138. The bottomsurface 134 of the second portion 98 interfaces with the top surface 106of the first portion 94 to enclose the composition 18 within the recess114.

The first portion 94 comprises an impermeable polymer 22 as discussedabove. The impermeable polymer 22 does not allow the passage of theactive agent and provides mechanical strength for the device 90. Theimpermeable polymer 22 suitably has a thickness of about 50 micrometersto about 800 micrometers or about 100 micrometers to about 250micrometers, depending on the overall size and required mechanicalstrength of the device 90.

The second portion 98 comprises a rate-limiting water-permeable polymer30 as discussed above. The rate-limiting water-permeable polymer 30 is apolymer that allows for the passage of the active agent and water ortissue fluids. The composition and/or thickness of this polymerdetermines the rate of release from the drug delivery device. Therate-limiting water-permeable polymer 30 suitably has a thickness ofabout 20 micrometers to about 500 micrometers, depending on the overallsize and required mechanical strength of the device 90.

FIGS. 14-18 illustrate a drug delivery device 146 according to anotherembodiment of the present invention. The drug delivery device 146 isgenerally cylindrical-shaped and includes a first portion 150 and asecond portion 154. The first portion 150 includes a bottom surface 158,a top surface 162, and an outer side surface 166 positioned between andextending around a periphery of the bottom surface 158 and the topsurface 162. The first portion 150 includes a recess 170 defined by aninner side wall 174 and a bottom surface 178. The bottom surface 178 ispositioned a predetermined distance from the bottom surface 158.

The recess 170 is configured to support the composition 18 comprising anactive agent (as discussed above). The dimensions of the recess 170 aresimilar to the dimensions of the composition 18 such that thecomposition 18 (in its undissolved state or pre-insertion state) cannotmove freely within the recess 170. The inner side wall 174 is generallyconcentric with the outer side surface 166 and is spaced from the outerside surface 166 around its entire circumference. The outer side surface166 includes a first diameter 182, and the inner side wall 174 includesa second diameter 186. The first diameter 182 is generally greater thanthe second diameter 186.

The second portion 154 includes a bottom surface 190, a top surface 194,and a side surface 198 positioned between and extending around aperiphery of the bottom surface 190 and the top surface 194. The bottomsurface 190 of the second portion 154 interfaces with the top surface162 of the first portion 150 to enclose the composition 18 within therecess 170.

The first portion 150 comprises an impermeable polymer 22 as discussedabove. The impermeable polymer 22 does not allow the passage of theactive agent and provides mechanical strength for the device 146. Theimpermeable polymer 22 suitably has a thickness of about 50 micrometersto about 800 micrometers or about 100 micrometers to about 250micrometers, depending on the overall size and required mechanicalstrength of the device 146.

The second portion 154 comprises a rate-limiting water-permeable polymer30 as discussed above. The rate-limiting water-permeable polymer 30 is apolymer that allows for the passage of the active agent and water ortissue fluids. The composition and/or thickness of this polymerdetermines the rate of release from the drug delivery device. Therate-limiting water-permeable polymer 30 suitably has a thickness ofabout 20 micrometers to about 500 micrometers, depending on the overallsize and required mechanical strength of the device 146.

FIGS. 19-24 illustrate a drug delivery device 202 according to anotherembodiment of the present invention. The drug delivery device 202 isgenerally cylindrical-shaped and includes a first portion 206 and asecond portion 210. The first portion 206 includes a bottom surface 214,a top surface 218, and an outer side surface 222 positioned between andextending around a periphery of the bottom surface 214 and the topsurface 218. The first portion 206 includes a recess 226 defined by aninner side wall 230 and a bottom surface 234. The bottom surface 234 ispositioned a predetermined distance from the bottom surface 214.

The recess 226 is configured to support the composition 18 comprising anactive agent (as discussed above). The dimensions of the recess 226 aresimilar to the dimensions of the composition 18 such that thecomposition 18 (in its undissolved state or pre-insertion state) cannotmove freely within the recess 226. The inner side wall 230 is generallyconcentric with the outer side surface 222 and is spaced from the outerside surface 222 around its entire circumference. The outer side surface222 includes a first diameter 234, and the inner side wall 230 includesa second diameter 238. The first diameter 234 is generally greater thanthe second diameter 238.

The second portion 210 includes a bottom surface 242, a top surface 246,and a side surface 250 positioned between and extending around aperiphery of the bottom surface 242 and the top surface 246. The bottomsurface 242 of the second portion 210 interfaces with the top surface246 of the first portion 206 to enclose the composition 18 within therecess 226.

The device 202 also includes a flange 254 such as a surgical suture tabconfigured to secure the device to an anchor point with a surgicalsuture(s). The flange 254 is connected to the second portion 210 andextends therefrom. The flange 254 includes a base 258, a first arm 262extending from the base 258, and a second arm 266 extending from thebase 258. The base 258 and the first and second arms 262, 266 areintegrally molded and form a recess 270 configured to receive at least aportion of the second portion 210. In one construction, the recess 270is configured to receive about one-half the circumference of the sidesurface 250. In other constructions, the recess 270 can be configured toreceive more or less than one-half the circumference of the side surface250. The base 258 can include one or more apertures 274 configured toreceive a surgical suture. The apertures 274 are not necessary, however,as a surgical suture needle can penetrate the flange 254 to secure thedevice 202 in a suitable position. The recess 270 of the flange 254 isconnected to side surface 250 of the second portion 210 in a thermalprocess that involves the application of heat to fuse the flange 254 tothe side surface 250. A suitable application of heat is in the range ofabout 90 degrees C. to about 102 degrees C. to fuse the flange 254 tothe side surface 250.

The first portion 206 comprises an impermeable polymer 22 as discussedabove. The impermeable polymer 22 does not allow the passage of theactive agent and provides mechanical strength for the device 202. Theimpermeable polymer 22 suitably has a thickness of about 50 micrometersto about 800 micrometers or about 100 micrometers to about 250micrometers, depending on the overall size and required mechanicalstrength of the device 202.

The second portion 210 comprises a rate-limiting water-permeable polymer30 as discussed above. The rate-limiting water-permeable polymer 30 is apolymer that allows for the passage of the active agent and water ortissue fluids. The composition and/or thickness of this polymerdetermines the rate of release from the drug delivery device. Therate-limiting water-permeable polymer 30 suitably has a thickness ofabout 20 micrometers to about 500 micrometers, depending on the overallsize and required mechanical strength of the device 202.

FIGS. 25-30 illustrate a drug delivery device 278 according to anotherembodiment of the present invention. The drug delivery device 278 isgenerally cylindrical-shaped and includes a first portion 282 and asecond portion 286. The first portion 282 includes a bottom surface 290,a top surface 294, and an outer side surface 298 positioned between andextending around a periphery of the bottom surface 290 and the topsurface 294. The first portion 282 includes a recess 302 defined by aninner side wall 306 and a bottom surface 310. The bottom surface 310 ispositioned a predetermined distance from the bottom surface 290.

The recess 302 is configured to support the composition 18 comprising anactive agent (as discussed above). The dimensions of the recess 302 aresimilar to the dimensions of the composition 18 such that thecomposition 18 (in its undissolved state or pre-insertion state) cannotmove freely within the recess 302. The inner side wall 306 is generallyconcentric with the outer side surface 298 and is spaced from the outerside surface 298 around its entire circumference. The outer side surface298 includes a first diameter 314, and the inner side wall 306 includesa second diameter 318. The first diameter 314 is generally greater thanthe second diameter 318.

The second portion 286 includes a bottom surface 322, a top surface 326,and a side surface 330 positioned between and extending around aperiphery of the bottom surface 322 and the top surface 326. The bottomsurface 322 of the second portion 286 interfaces with the top surface294 of the first portion 284 to enclose the composition 18 within therecess 302.

The device 278 also includes a flange 334 such as a surgical suture tabconfigured to secure the device to an anchor point with a surgicalsuture(s). The flange 334 is connected to the second portion 286 andextends therefrom. The flange 334 includes a base 338, a first arm 342extending from the base 338, and a second arm 346 extending from thebase 338. The base 338 and the first and second arms 342, 346 areintegrally molded and form a recess 350 configured to receive at least aportion of the second portion 286. In one construction, the recess 350is configured to receive about one-half the circumference of the sidesurface 330. In other constructions, the recess 350 can be configured toreceive more or less than one-half the circumference of the side surface330. The base 338 can include one or more apertures 354 configured toreceive a surgical suture. The apertures 354 are not necessary, however,as a surgical suture needle can penetrate the flange 334 to secure thedevice 278 in a suitable position. The recess 350 of the flange 334 isconnected to side surface 330 of the second portion 286 in a thermalprocess that involves the application of heat to fuse the flange 334 tothe side surface 330. A suitable application of heat is in the range ofabout 90 degrees C. to about 102 degrees C. to fuse the flange 334 tothe side surface 330.

The first portion 282 comprises an impermeable polymer 22 as discussedabove. The impermeable polymer 22 does not allow the passage of theactive agent and provides mechanical strength for the device 278. Theimpermeable polymer 22 suitably has a thickness of about 50 micrometersto about 800 micrometers or about 100 micrometers to about 250micrometers, depending on the overall size and required mechanicalstrength of the device 278.

The second portion 286 comprises a rate-limiting water-permeable polymer30 as discussed above. The rate-limiting water-permeable polymer 30 is apolymer that allows for the passage of the active agent and water ortissue fluids. The composition and/or thickness of this polymerdetermines the rate of release from the drug delivery device. Therate-limiting water-permeable polymer 30 suitably has a thickness ofabout 20 micrometers to about 500 micrometers, depending on the overallsize and required mechanical strength of the device 278.

FIGS. 31-35 illustrate a drug delivery device 358 according to anotherembodiment of the present invention. The drug delivery device 358 isgenerally cylindrical-shaped and includes a first portion 362 and asecond portion 366. The first portion 362 includes a bottom surface 370,a top surface 374, and an outer side surface 378 positioned between andextending around a periphery of the bottom surface 370 and the topsurface 374. The first portion 362 includes a recess 382 defined by aninner side wall 386 and a bottom surface 390. The bottom surface 390 ispositioned a predetermined distance from the bottom surface 370.

The recess 382 is configured to support the composition 18 comprising anactive agent (as discussed above). The dimensions of the recess 382 aresimilar to the dimensions of the composition 18 such that thecomposition 18 (in its undissolved state or pre-insertion state) cannotmove freely within the recess 382. The inner side wall 386 is generallyconcentric with the outer side surface 378 and is spaced from the outerside surface 378 around its entire circumference. The outer side surface378 includes a first diameter 394, and the inner side wall 386 includesa second diameter 398. The first diameter 394 is generally greater thanthe second diameter 398.

The second portion 366 includes a bottom surface 402, a top surface 406,and a side surface 410 positioned between and extending around aperiphery of the bottom surface 402 and the top surface 406. The bottomsurface 402 of the second portion 366 interfaces with the top surface374 of the first portion 362 to enclose the composition 18 within therecess 382. The second portion 366 includes a base 414 and a portion 418extending from the base 414. The portion 418 also at least partiallyextends outside of the side surface 378. The portion 418 can include oneor more apertures 422 configured to receive a surgical suture. Theapertures 422 are not necessary, however, as a surgical suture needlecan penetrate the portion 418 to secure the device 358 in a suitableposition. The bottom surface 402 of the second portion 366 is connectedto the top surface 374 of the first portion 362 in a thermal processthat involves the application of heat to fuse the bottom surface 402 tothe top surface 374. A suitable application of heat is in the range ofabout 90 degrees C. to about 102 degrees C. to fuse the bottom surface402 to the top surface 374.

The first portion 362 comprises an impermeable polymer 22 as discussedabove. The impermeable polymer 22 does not allow the passage of theactive agent and provides mechanical strength for the device 358. Theimpermeable polymer 22 suitably has a thickness of about 50 micrometersto about 800 micrometers or about 100 micrometers to about 250micrometers, depending on the overall size and required mechanicalstrength of the device 358.

The second portion 366 (including the portion 418) comprises arate-limiting water-permeable polymer 30 as discussed above. Therate-limiting water-permeable polymer 30 is a polymer that allows forthe passage of the active agent and water or tissue fluids. Thecomposition and/or thickness of this polymer determines the rate ofrelease from the drug delivery device. The rate-limiting water-permeablepolymer 30 suitably has a thickness of about 20 micrometers to about 500micrometers, depending on the overall size and required mechanicalstrength of the device 358.

FIGS. 36-40 illustrate a drug delivery device 426 according to anotherembodiment of the present invention. The drug delivery device 426 isgenerally cylindrical-shaped and includes a first portion 430 and asecond portion 434. The first portion 430 includes a bottom surface 438,a top surface 442, and an outer side surface 446 positioned between andextending around a periphery of the bottom surface 438 and the topsurface 442. The first portion 430 includes a recess 450 defined by aninner side wall 454 and a bottom surface 458. The bottom surface 458 ispositioned a predetermined distance from the bottom surface 438.

The recess 450 is configured to support the composition 18 comprising anactive agent (as discussed above). The dimensions of the recess 450 aresimilar to the dimensions of the composition 18 such that thecomposition 18 (in its undissolved state or pre-insertion state) cannotmove freely within the recess 450. The inner side wall 454 is generallyconcentric with the outer side surface 446 and is spaced from the outerside surface 446 around its entire circumference. The outer side surface446 includes a first diameter 462, and the inner side wall 454 includesa second diameter 466. The first diameter 462 is generally greater thanthe second diameter 466.

The second portion 434 includes a bottom surface 470, a top surface 474,and a side surface 478 positioned between and extending around aperiphery of the bottom surface 470 and the top surface 474. The bottomsurface 470 of the second portion 434 interfaces with the top surface442 of the first portion 430 to enclose the composition 18 within therecess 450. The second portion 434 includes a base 482 and a portion 486extending from the base 482. The portion 486 also at least partiallyextends outside of the side surface 446. The portion 486 can include oneor more apertures 490 configured to receive a surgical suture. Theapertures 490 are not necessary, however, as a surgical suture needlecan penetrate the portion 486 to secure the device 426 in a suitableposition. The bottom surface 470 of the second portion 434 is connectedto the top surface 442 of the first portion 430 in a thermal processthat involves the application of heat to fuse the bottom surface 470 tothe top surface 442. A suitable application of heat is in the range ofabout 90 degrees C. to about 102 degrees C. to fuse the bottom surface470 to the top surface 442.

The first portion 430 comprises an impermeable polymer 22 as discussedabove. The impermeable polymer 22 does not allow the passage of theactive agent and provides mechanical strength for the device 426. Theimpermeable polymer 22 suitably has a thickness of about 50 micrometersto about 800 micrometers or about 100 micrometers to about 250micrometers, depending on the overall size and required mechanicalstrength of the device 426.

The second portion 434 (including the portion 486) comprises arate-limiting water-permeable polymer 30 as discussed above. Therate-limiting water-permeable polymer 30 is a polymer that allows forthe passage of the active agent and water or tissue fluids. Thecomposition and/or thickness of this polymer determines the rate ofrelease from the drug delivery device. The rate-limiting water-permeablepolymer 30 suitably has a thickness of about 20 micrometers to about 500micrometers, depending on the overall size and required mechanicalstrength of the device 426.

FIGS. 41-45 illustrate a drug delivery device 494 according to anotherembodiment of the present invention. The drug delivery device 494 isgenerally cylindrical-shaped and includes a base portion 498, a middleportion 502, and an upper portion 506. The base portion 498 includes abottom surface 510, an upper surface 514, and a side wall 518 positionedbetween the bottom surface 510 and the upper surface 514 and extendingaround a periphery of the bottom surface 510 and the upper surface 514.The side wall 518 includes a first diameter 522.

The middle portion 502 includes a bottom wall 526, a top wall 528, anouter side wall 530 having a second diameter 534 substantially the sameas the first diameter 522, and an inner side wall 538 having a thirddiameter 542 less than the second diameter 534. The inner side wall 538is generally concentric with the outer side wall 530 and is spaced fromthe outer side wall 530 around its entire circumference. The bottom wall526 rests upon or is in contact with the upper surface 514 of the baseportion 498. The middle portion 502 includes an aperture 546 in thebottom wall 526 and the top wall 528 and is surrounded by the inner sidewall 538. The aperture 546 (and the upper surface 514) is configured tosupport the composition 18 comprising an active agent (as discussedabove).

The upper portion 506 includes a bottom surface 550, an upper surface554, and a side wall 558 positioned between the bottom surface 550 andthe upper surface 554 and extending around a periphery of the bottomsurface 550 and the upper surface 554. The bottom surface 550 rests onor is in contact with the middle portion 502 such that the composition18 is housed within an enclosure 562 defined at least partially by theupper surface 514, the inner side wall 538, and at least a portion ofthe bottom surface 550. The side wall 558 includes a fourth diameter 566substantially the same as the first diameter 522. The dimensions of theenclosure 562 are similar to the dimensions of the composition 18 suchthat the composition 18 (in its undissolved state or pre-insertionstate) cannot move freely within the enclosure 562.

The base portion 498, the middle portion 502, and the upper portion 506comprise a rate-limiting water-permeable polymer 30 as discussed above.The rate-limiting water-permeable polymer 30 is a polymer that allowsfor the passage of the active agent and water or tissue fluids. Thecomposition and/or thickness of this polymer determines the rate ofrelease from the drug delivery device. The rate-limiting water-permeablepolymer 30 suitably has a thickness of about 20 micrometers to about 500micrometers, depending on the overall size and required mechanicalstrength of the device 494.

FIGS. 46-50 illustrate a drug delivery device 570 according to anotherembodiment of the present invention. The drug delivery device 570 isgenerally cylindrical-shaped and includes a base portion 574, a middleportion 578, and an upper portion 582. The base portion 574 includes abottom surface 586, an upper surface 590, and a side wall 594 positionedbetween the bottom surface 586 and the upper surface 590 and extendingaround a periphery of the bottom surface 586 and the upper surface 590.The side wall 594 includes a first diameter 598.

The middle portion 578 includes a bottom wall 602, a top wall 604, anouter side wall 606 having a second diameter 610 substantially the sameas the first diameter 598, and an inner side wall 614 having a thirddiameter 618 less than the second diameter 610. The inner side wall 614is generally concentric with the outer side wall 606 and is spaced fromthe outer side wall 606 around its entire circumference. The bottom wall602 rests upon or is in contact with the upper surface 590 of the baseportion 574. The middle portion 578 includes an aperture 622 in thebottom wall 602 and the top wall 604 and is surrounded by the inner sidewall 614. The aperture 622 (and the upper surface 590) is configured tosupport the composition 18 comprising an active agent (as discussedabove).

The upper portion 582 includes a bottom surface 626, an upper surface630, and a side wall 634 positioned between the bottom surface 626 andthe upper surface 630 and extending around a periphery of the bottomsurface 626 and the upper surface 630. The bottom surface 626 rests onor is in contact with the middle portion 578 such that the composition18 is housed within an enclosure 638 defined at least partially by theupper surface 590, the inner side wall 614, and at least a portion ofthe bottom surface 626. The side wall 634 includes a fourth diameter 642substantially the same as the first diameter 598. The dimensions of theenclosure 638 are similar to the dimensions of the composition 18 suchthat the composition 18 (in its undissolved state or pre-insertionstate) cannot move freely within the enclosure 638.

The base portion 574, the middle portion 578, and the upper portion 582comprise a rate-limiting water-permeable polymer 30 as discussed above.The rate-limiting water-permeable polymer 30 is a polymer that allowsfor the passage of the active agent and water or tissue fluids. Thecomposition and/or thickness of this polymer determines the rate ofrelease from the drug delivery device. The rate-limiting water-permeablepolymer 30 suitably has a thickness of about 20 micrometers to about 500micrometers, depending on the overall size and required mechanicalstrength of the device 570.

FIGS. 51-55 illustrate a drug delivery device 646 according to anotherembodiment of the present invention. The drug delivery device 646 isgenerally cylindrical-shaped and includes a base portion 650, a middleportion 654, and an upper portion 658. The base portion 650 includes abottom surface 662, an upper surface 670, and a side wall 674 positionedbetween the bottom surface 662 and the upper surface 670 and extendingaround a periphery of the bottom surface 662 and the upper surface 670.The side wall 674 includes a first diameter 678.

The middle portion 654 includes a bottom wall 682, a top wall 684, anouter side wall 686 having a second diameter 690 substantially the sameas the first diameter 678, and an inner side wall 694 having a thirddiameter 698 less than the second diameter 690. The inner side wall 694is generally concentric with the outer side wall 686 and is spaced fromthe outer side wall 686 around its entire circumference. The bottom wall682 rests upon or is in contact with the upper surface 670 of the baseportion 650. The middle portion 654 includes an aperture 702 in thebottom wall 682 and the top wall 684 and is surrounded by the inner sidewall 694. The aperture 702 (and the upper surface 670) is configured tosupport the composition 18 comprising an active agent (as discussedabove).

The upper portion 658 includes a bottom surface 706, an upper surface710, and a side wall 714 positioned between the bottom surface 706 andthe upper surface 710 and extending around a periphery of the bottomsurface 706 and the upper surface 710. The bottom surface 706 rests onor is in contact with the middle portion 654 such that the composition18 is housed within an enclosure 718 defined at least partially by theupper surface 670, the inner side wall 694, and at least a portion ofthe bottom surface 706. The side wall 714 includes a fourth diameter 722substantially the same as the first diameter 678. The dimensions of theenclosure 718 are similar to the dimensions of the composition 18 suchthat the composition 18 (in its undissolved state or pre-insertionstate) cannot move freely within the enclosure 718.

The middle portion 654 comprises an impermeable polymer 22 as discussedabove. The impermeable polymer 22 does not allow the passage of theactive agent and provides mechanical strength for the device 646. Theimpermeable polymer 22 suitably has a thickness of about 50 micrometersto about 800 micrometers or about 100 micrometers to about 250micrometers, depending on the overall size and required mechanicalstrength of the device 646.

The base portion 650, the middle portion 654, and the upper portion 658comprise a rate-limiting water-permeable polymer 30 as discussed above.The rate-limiting water-permeable polymer 30 is a polymer that allowsfor the passage of the active agent and water or tissue fluids. Thecomposition and/or thickness of this polymer determines the rate ofrelease from the drug delivery device. The rate-limiting water-permeablepolymer 30 suitably has a thickness of about 20 micrometers to about 500micrometers, depending on the overall size and required mechanicalstrength of the device 646.

FIGS. 56-60 illustrate a drug delivery device 726 according to anotherembodiment of the present invention. The drug delivery device 726 isgenerally cylindrical-shaped and includes a base portion 730, a middleportion 734, and an upper portion 738. The base portion 730 includes abottom surface 742, an upper surface 746, and a side wall 750 positionedbetween the bottom surface 742 and the upper surface 746 and extendingaround a periphery of the bottom surface 742 and the upper surface 746.The side wall 750 includes a first diameter 754.

The middle portion 734 includes a bottom wall 758, a top wall 760, anouter side wall 762 having a second diameter 766 substantially the sameas the first diameter 754, and an inner side wall 770 having a thirddiameter 774 less than the second diameter 766. The inner side wall 770is generally concentric with the outer side wall 762 and is spaced fromthe outer side wall 762 around its entire circumference. The bottom wall758 rests upon or is in contact with the upper surface 746 of the baseportion 730. The middle portion 734 includes an aperture 778 in thebottom wall 758 and the top wall 760 and is surrounded by the inner sidewall 770. The aperture 778 (and the upper surface 746) is configured tosupport the composition 18 comprising an active agent (as discussedabove).

The upper portion 738 includes a bottom surface 782, an upper surface786, and a side wall 790 positioned between the bottom surface 782 andthe upper surface 786 and extending around a periphery of the bottomsurface 782 and the upper surface 786. The bottom surface 782 rests onor is in contact with the middle portion 734 such that the composition18 is housed within an enclosure 794 defined at least partially by theupper surface 746, the inner side wall 770, and at least a portion ofthe bottom surface 782. The side wall 790 includes a fourth diameter 798substantially the same as the first diameter 754. The dimensions of theenclosure 794 are similar to the dimensions of the composition 18 suchthat the composition 18 (in its undissolved state or pre-insertionstate) cannot move freely within the enclosure 794.

The base portion 730, the middle portion 734, and the upper portion 738comprise a rate-limiting water-permeable polymer 30 as discussed above.The rate-limiting water-permeable polymer 30 is a polymer that allowsfor the passage of the active agent and water or tissue fluids. Thecomposition and/or thickness of this polymer determines the rate ofrelease from the drug delivery device. The rate-limiting water-permeablepolymer 30 suitably has a thickness of about 20 micrometers to about 500micrometers, depending on the overall size and required mechanicalstrength of the device 726.

FIGS. 61-65 illustrate a drug delivery device 802 according to anotherembodiment of the present invention. The drug delivery device 802 isgenerally cylindrical-shaped and includes a base portion 806, a middleportion 810, and an upper portion 814. The base portion 806 includes abottom surface 818, an upper surface 822, and a side wall 826 positionedbetween the bottom surface 818 and the upper surface 822 and extendingaround a periphery of the bottom surface 818 and the upper surface 822.The side wall 826 includes a first diameter 830.

The middle portion 810 includes a bottom wall 834, a top wall 836, anouter side wall 838 having a second diameter 842 substantially the sameas the first diameter 830, and an inner side wall 846 having a thirddiameter 850 less than the second diameter 842. The inner side wall 846is generally concentric with the outer side wall 838 and is spaced fromthe outer side wall 838 around its entire circumference. The bottom wall834 rests upon or is in contact with the upper surface 822 of the baseportion 806. The middle portion 810 includes an aperture 854 in thebottom wall 834 and the top wall 836 and is surrounded by the inner sidewall 846. The aperture 854 (and the upper surface 822) is configured tosupport the composition 18 comprising an active agent (as discussedabove).

The upper portion 814 includes a bottom surface 858, an upper surface862, and a side wall 866 positioned between the bottom surface 858 andthe upper surface 862 and extending around a periphery of the bottomsurface 858 and the upper surface 862. The bottom surface 858 rests onor is in contact with the middle portion 810 such that the composition18 is housed within an enclosure 870 defined at least partially by theupper surface 822, the inner side wall 846, and at least a portion ofthe bottom surface 858. The side wall 866 includes a fourth diameter 874substantially the same as the first diameter 830. The dimensions of theenclosure 870 are similar to the dimensions of the composition 18 suchthat the composition 18 (in its undissolved state or pre-insertionstate) cannot move freely within the enclosure 870.

The base portion 806, the middle portion 810, and the upper portion 814comprise a rate-limiting water-permeable polymer 30 as discussed above.The rate-limiting water-permeable polymer 30 is a polymer that allowsfor the passage of the active agent and water or tissue fluids. Thecomposition and/or thickness of this polymer determines the rate ofrelease from the drug delivery device. The rate-limiting water-permeablepolymer 30 suitably has a thickness of about 20 micrometers to about 500micrometers, depending on the overall size and required mechanicalstrength of the device 802.

FIGS. 66-70 illustrate a drug delivery device 880 according to anotherembodiment of the present invention. The drug delivery device 880 isgenerally elliptical-shaped and is adapted to conform to the curvatureof the eye. The materials of the drug delivery device 880 includesuitable properties that provide flexibility to allow the device 880 toflex and conform to the curvature or shape of the eye. The drug deliverydevice 880 includes a base portion 884, a middle portion 888, and anupper portion 892. The base portion 884 includes a bottom surface 896,an upper surface 900, and a side wall 904 positioned between the bottomsurface 896 and the upper surface 900 and extending around a peripheryof the bottom surface 896 and the upper surface 900.

The middle portion 888 includes a bottom wall 908, a top wall 910, anouter side wall 912, and an inner side wall 916. The inner side wall 916is spaced from the outer side wall 912. The bottom wall 908 rests uponor is in contact with the upper surface 900 of the base portion 884. Themiddle portion 888 includes an aperture 920 in the bottom wall 908 andthe top wall 910 and is surrounded by the inner side wall 916. Theaperture 920 (and the upper surface 900) is configured to support thecomposition 18 comprising an active agent (as discussed above). Theaperture 920 is generally circular-shaped as illustrated, however theaperture 920 may have a different but suitable shape to accommodate theshape of the composition 18. For example, the aperture 920 may beelliptical-shaped similar to the outer side wall 912. The aperture 920may be concentric or non-concentric with the outer side wall 912.

The upper portion 892 includes a bottom surface 924, an upper surface928, and a side wall 932 positioned between the bottom surface 924 andthe upper surface 928 and extending around a periphery of the bottomsurface 924 and the upper surface 928. The bottom surface 924 rests onor is in contact with the middle portion 888 such that the composition18 is housed within an enclosure 936 defined at least partially by theupper surface 900, the inner side wall 916, and at least a portion ofthe bottom surface 924. The dimensions of the enclosure 936 are similarto the dimensions of the composition 18 such that the composition 18 (inits undissolved state or pre-insertion state) cannot move freely withinthe enclosure 936.

The base portion 884, the middle portion 888, and the upper portion 892comprise a rate-limiting water-permeable polymer 30 as discussed above.The rate-limiting water-permeable polymer 30 is a polymer that allowsfor the passage of the active agent and water or tissue fluids. Thecomposition and/or thickness of this polymer determines the rate ofrelease from the drug delivery device. The rate-limiting water-permeablepolymer 30 suitably has a thickness of about 20 micrometers to about 500micrometers, depending on the overall size and required mechanicalstrength of the device 880.

FIGS. 71-75 illustrate a drug delivery device 950 according to anotherembodiment of the present invention. The drug delivery device 950 isgenerally elliptical-shaped and is adapted to conform to the curvatureof the eye. The materials of the drug delivery device 950 includesuitable properties that provide flexibility to allow the device 950 toflex and conform to the curvature or shape of the eye. The drug deliverydevice 950 includes a base portion 954, a middle portion 958, and anupper portion 962. The base portion 954 includes a bottom surface 966,an upper surface 970, and a side wall 974 positioned between the bottomsurface 966 and the upper surface 970 and extending around a peripheryof the bottom surface 966 and the upper surface 970.

The middle portion 958 includes a bottom wall 978, a top wall 980, anouter side wall 982, a first inner side wall 986 and a second inner sidewall 990. The first and second inner side walls 986, 990 are spaced fromthe outer side wall 982. The bottom wall 978 rests upon or is in contactwith the upper surface 970 of the base portion 954. The middle portion958 includes a first aperture 994 and a second aperture 998 in thebottom wall 978 and the top wall 980 and is surrounded by the firstinner side wall 986 and the second inner side wall 990, respectively.The apertures 994, 998 (and the upper surface 970) are configured tosupport one or more of the composition 18 comprising an active agent (asdiscussed above). Each of the compositions 18 can comprise the sameagents or different agents or other types of elements that comprise thecomposition(s) 18. The apertures 994, 998 are generally circular-shapedas illustrated, however one or more of the apertures 994, 998 may have adifferent but suitable shape to accommodate the shape of thecomposition(s) 18. For example, one or both of the apertures 994, 998may be elliptical-shaped similar to the outer side wall 982. One or bothof the apertures 994, 998 may be concentric or non-concentric with theouter side wall 982.

The upper portion 962 includes a bottom surface 1002, an upper surface1006, and a side wall 1010 positioned between the bottom surface 1002and the upper surface 1006 and extending around a periphery of thebottom surface 1002 and the upper surface 1006. The bottom surface 1002rests on or is in contact with the middle portion 958 such that thecompositions 18 are housed within a first enclosure 1014 and a secondenclosure 1018 defined at least partially by the upper surface 970, theinner side walls 986, 990, and at least a portion of the bottom surface1002. The dimensions of the enclosures 1014, 1018 are similar to thedimensions of the compositions 18 such that the compositions 18 (in itsundissolved state or pre-insertion state) cannot move freely within theenclosures 1014, 1018.

The base portion 954, the middle portion 958, and the upper portion 962comprise a rate-limiting water-permeable polymer 30 as discussed above.The rate-limiting water-permeable polymer 30 is a polymer that allowsfor the passage of the active agent and water or tissue fluids. Thecomposition and/or thickness of this polymer determines the rate ofrelease from the drug delivery device. The rate-limiting water-permeablepolymer 30 suitably has a thickness of about 20 micrometers to about 500micrometers, depending on the overall size and required mechanicalstrength of the device 950.

FIGS. 76-80 illustrate a drug delivery device 1030 according to anotherembodiment of the present invention. The drug delivery device 1030 isgenerally elliptical-shaped and is adapted to conform to the curvatureof the eye. In this construction, the ends of the device 1030 arerounded in comparison to the device 880 described (and illustrated inFIGS. 66-70) above. The materials of the drug delivery device 1030include suitable properties that provide flexibility to allow the device1030 to flex and conform to the curvature or shape of the eye. The drugdelivery device 1030 includes a base portion 1034, a middle portion1038, and an upper portion 1042. The base portion 1034 includes a bottomsurface 1046, an upper surface 1050, and a side wall 1054 positionedbetween the bottom surface 1046 and the upper surface 1050 and extendingaround a periphery of the bottom surface 1046 and the upper surface1050.

The middle portion 1038 includes a bottom wall 1058, a top wall 1062, anouter side wall 1066, and an inner side wall 1070. The inner side wall1070 is spaced from the outer side wall 1066. The bottom wall 1058 restsupon or is in contact with the upper surface 1050 of the base portion1034. The middle portion 1038 includes an aperture 1074 in the bottomwall 1058 and the top wall 1062 and is surrounded by the inner side wall1070. The aperture 1074 (and the upper surface 1050) is configured tosupport the composition 18 comprising an active agent (as discussedabove). The aperture 1074 is generally circular-shaped as illustrated,however the aperture 1074 may have a different but suitable shape toaccommodate the shape of the composition 18. For example, the aperture1074 may be elliptical-shaped similar to the outer side wall 1066. Theaperture 1074 may be concentric or non-concentric with the outer sidewall 1066.

The upper portion 1042 includes a bottom surface 1078, an upper surface1082, and a side wall 1086 positioned between the bottom surface 1078and the upper surface 1082 and extending around a periphery of thebottom surface 1078 and the upper surface 1082. The bottom surface 1078rests on or is in contact with the middle portion 1038 such that thecomposition 18 is housed within an enclosure 1090 defined at leastpartially by the upper surface 1050, the inner side wall 1070, and atleast a portion of the bottom surface 1078. The dimensions of theenclosure 1090 are similar to the dimensions of the composition 18 suchthat the composition 18 (in its undissolved state or pre-insertionstate) cannot move freely within the enclosure 1090.

The base portion 1034, the middle portion 1038, and the upper portion1042 comprise a rate-limiting water-permeable polymer 30 as discussedabove. The rate-limiting water-permeable polymer 30 is a polymer thatallows for the passage of the active agent and water or tissue fluids.The composition and/or thickness of this polymer determines the rate ofrelease from the drug delivery device. The rate-limiting water-permeablepolymer 30 suitably has a thickness of about 20 micrometers to about 500micrometers, depending on the overall size and required mechanicalstrength of the device 1030.

In some embodiments, the non-bioabsorbable polymer structure contains apigment. The pigment is optionally placed into the impermeable polymer.Suitable pigments include, but are not limited to, inorganic pigments,organic lake pigments, pearlescent pigments, fluorescein, and mixturesthereof. Inorganic pigments useful in this invention include thoseselected from the group consisting of rutile or anatase titaniumdioxide, coded in the Color Index under the reference CI 77,891; black,yellow, red and brown iron oxides, coded under references CI 77,499,77,492 and, 77,491; manganese violet (CI 77,742); ultramarine blue (CI77,007); chromium oxide (CI 77,288); chromium hydrate (CI 77,289); andferric blue (CI 77,510) and mixtures thereof.

The organic pigments and lakes useful in this invention include thoseselected from the group consisting of D&C Red No. 19 (CI 45,170), D&CRed No. 9 (CI 15,585), D&C Red No. 21 (CI 45,380), D&C Orange No. 4 (CI15,510), D&C Orange No. 5 (CI 45,370), D&C Red No. 27 (CI 45,410), D&CRed No. 13 (CI 15,630), D&C Red No. 7 (CI 15,850), D&C Red No. 6 (CI15,850), D&C Yellow No. 5 (CI 19,140), D&C Red No. 36 (CI 12,085), D&COrange No. 10 (CI 45,425), D&C Yellow No. 6 (CI 15,985), D&C Red No. 30(CI 73,360), D&C Red No. 3 (CI 45,430), the dye or lakes based onCochineal Carmine (CI 75,570) and mixtures thereof.

The pearlescent pigments useful in this invention include those selectedfrom the group consisting of the white pearlescent pigments such as micacoated with titanium oxide, bismuth oxychloride, colored pearlescentpigments such as titanium mica with iron oxides, titanium mica withferric blue, chromium oxide and the like, titanium mica with an organicpigment of the above-mentioned type as well as those based on bismuthoxychloride and mixtures thereof.

In a further embodiment, the drug delivery device comprises acomposition comprising an active agent at least partially encompassed byan impermeable membrane and a permeable membrane, wherein the permeablemembrane controls release of the active agent episclerally over time.

About 70% to about 90% of the active agent is suitably released from thedrug delivery device over a period of about 30 days to about 5 years.Alternatively, about 70% to about 90% of the active agent is releasedover a period of about 30 days to about 2 years or about 30 days toabout 1 year or about 30 days to about 90 days or about 1 year to about5 years or about 1 year to about 2 years.

In some embodiments, the active agent is released from any one of thedrug delivery devices at a rate of about 0.0003 micrograms/hr or fromabout 0.0001 micrograms/hr to about 200 micrograms/hr, or from about0.0001 micrograms/hr to about 30 micrograms/hr, or from about 0.001micrograms/hr to about 30 micrograms/hr, or from about 0.001micrograms/hr to about 10 micrograms/hr.

Suitably, the rate of release of the active agent does not deviatesubstantially from linearity (i.e., does not deviate from linearity morethan about 5%) until at least about 70% and at most about 95% of theactive agent is released from the drug delivery device.

Alternatively, about 2% to about 90% of the active agent is releasedfrom the drug delivery device with a coefficient of determination,R-squared or R2, of the linear regression is at least about 0.95.

Dosages may be varied based on the active agent being used, the patientbeing treated, the condition being treated, the severity of thecondition being treated, the route of administration, etc. to achievethe desired effect.

The drug delivery devices of the present invention can be used to treatvarious conditions including, ocular conditions (such as glaucoma,ocular hypertension, ocular inflammation, uveitis, macular degenerativeconditions, retinal degenerative conditions, ocular tumors, ocularallergy, and dry eye), topical fungal infections, topical bacterialinfections, dermatitis, peripheral neuropathy, allergic and otherrashes, and topical eruptions oft-cell lymphoma. Some of the drugdelivery devices of the present invention are also useful in decreasingintraocular pressure. In addition to treatment of ocular conditions, thepresent invention can be used for local delivery of therapeutics tovarious types of solid tumors, including tumors of the lung, pancreas,liver, kidney, colon and brain.

The device can also be implanted subcutaneously, intramuscularly orintraperitoneally for systemic delivery of therapeutics, includingdelivery of contraceptive agents and agents to treat cardiovascular,metabolic, immunological and neurological disorders. The drug deliverydevice may be implanted at or near a tissue affected by the condition.The drug delivery devices of the present invention are suitablyimplanted in ocular tissues. In some embodiments, the drug deliverydevices are implanted episclerally (inserted between the conjunctiva andsclera) with the permeable portion of the polymer structure facing thesclera. The drug delivery devices of the present invention may also beused as supraconjunctival inserts. In some embodiments, the drugdelivery devices are placed on top of the bulbar conjunctiva near theconjunctival fornix. A suture may be used to immobilize the insert.

In some embodiments, the present invention is a method of treating anocular condition comprising episcleral or supraconjunctival placement ofa drug delivery device containing a composition comprising an activeagent, wherein the active agent is released at a rate of

Q=0.001×L×N×C

wherein C is the optimal topically effective concentration (inmicrograms/mL) of the active agent, L is the placement constant, and Nis the composition constant in mL/hour. L is 1 or 2 when the drugdelivery device is placed episclerally or supraconjunctivally,respectively. N=0.005 to 0.15 for prostaglandins in their ester, amide,free acid or salt form, N=0.02-0.6 for rho-kinase inhibitors in theirsalt or free base form, and N=0.05 to 1.5 for any other active agents.Using the equation, a prostaglandin active agent with a topicaleffective concentration of 0.05 milligrams/mL (e.g., latanoprost) may bedesigned to release at a rate of about 0.00025 to about 0.0075micrograms/hr or about 0.0005 to about 0.015 micrograms/hr when the drugdelivery device is placed episclerally or supraconjunctivally,respectively. Using a similar approach, a rho-kinase active agent with atopical effective concentration of 1 milligram/mL (e.g., a Y-39983 salt)may be designed to release at a rate of about 0.02 to about 0.6micrograms/hr or about 0.04 to about 1.2 micrograms/hr when the drugdelivery device is placed episclerally or supraconjunctivally,respectively. Again, using a similar approach, a non-prostaglandin,non-rho-kinase, active agent with a topical effective concentration of 5milligrams/mL (e.g., a timolol salt) may be designed to release at arate of about 0.25 to about 7.5 micrograms/hr or about 0.5 to about 15micrograms/hr when the drug delivery device is placed episclerally orsupraconjunctivally, respectively.

Brimonidine or its salts may be designed to release at a rate of about0.05 to about 60 micrograms/hr, about 0.75 to about 7.5 micrograms/hr,about 0.05 to about 10 micrograms/hr, about 0.05 to about 5micrograms/hr, about 0.05 to about 4 micrograms/hr, about 0.3 to about60 micrograms/hr, 0.1 to about 10 micrograms/hr, or 0.7 to about 2.5micrograms/hr. Brimonidine free base may be designed to release at arate of about 0.05 to about 4 micrograms/hr, 0.7 to about 2.5micrograms/hr, or 0.7 to about 2.5 micrograms/hr. Brimonidine tartratemay be designed to release at a rate of about 0.3 to about 60micrograms/hr, or 0.1 to about 10 micrograms/hr.

Timolol or its salts may be designed to release at a rate of about 0.1to about 50 micrograms/hr, about 1 to about 50 micrograms/hr, about 2.5to about 20 micrograms/hr, about 0.1 to about 20 micrograms/hr, about0.5 to about 5 micrograms/hr, or about 12 to about 18 micrograms/hr.Timolol maleate may be designed to release at a rate of about 1 to about50 micrograms/hr, about 0.5 to about 5 micrograms/hr, or about 12 toabout 18 micrograms/hr.

Latanoprost, latanoprost free acid, or its salts may be designed torelease at a rate of about 0.0001 to about 5 micrograms/hr, about 0.0005to about 0.025 micrograms/hr, about 0.04 to about 5 micrograms/hr, about0.0001 to about 0.05 micrograms/hr, about 0.001 to about 0.05micrograms/hr, or about 0.04 to about 5 micrograms/hr. Latanoprostarginine salt may be designed to release at a rate of about 0.04 toabout 5 micrograms/hr, or about 0.0001 to about 0.05 micrograms/hr.Latanoprost (the isopropyl ester of latanoprost fee acid) may bedesigned to release at a rate of about 0.001 to about 0.05micrograms/hr.

Travoprost, travoprost free acid, or its salts may be designed torelease at a rate of about 0.0001 to about 0.05 micrograms/hr, about0.0004 to about 0.02 micrograms/hr, about 0.0001 to about 0.05micrograms/hr, or about 0.001 to about 0.02 micrograms/hr. Travoprost(the isopropyl ester of travoprost free acid) may be designed to releaseat a rate of about 0.001 to about 0.02 micrograms/hr.

Dorzolamide or its salts may be designed to release at a rate of about0.1 to about 2 micrograms/hr.

Ethacrynic acid or its salts may be designed to release at a rate ofabout 5 to about 50 micrograms/hr.

AR-102, AR-102 free acid or its salts may be designed to release at arate of about 0.0005 to about 0.7 micrograms/hr, about 0.04 to about 0.7micrograms/hr, or about 0.0005 to about 0.1 micrograms/hr. AR-102 freeacid may be designed to release at a rate of about 0.04 to about 0.7micrograms/hr, or about 0.0005 to about 0.1 micrograms/hr.

Dexamethasone or its salts may be designed to release at a rate of about0.1 to about 200 micrograms/hr, about 0.1 to about 3 micrograms/hr,about 0.1 to about 5 micrograms/hr, or about 2 to about 200micrograms/hr. Dexamethasone sodium phosphate may be designed to releaseat a rate of about 2 to about 200 micrograms/hr, or about 0.1 to about 5micrograms/hr.

Bimatoprost, bimatoprost free acid or its salts may be designed torelease at a rate of about 0.0005 to about 0.1 micrograms/hr, or about0.002 to about 0.1 micrograms/hr.

The active agent may be any active agent suitable to treat the desiredcondition. In various embodiments, the active agent may be of one of lowsolubility, moderate solubility or high solubility. “Low solubility”means a solubility of less than or equal to 300 micrograms/mL inphosphate buffered saline (PBS) at pH=7.2-7.4. Examples include, but arenot limited to, cyclosporin A, lovastatin, atorvastatin, dexamethasone,and travoprost isopropyl ester, latanoprost isopropyl ester. “Moderatesolubility” means a solubility of greater than 300 micrograms/mL, butless than 1000 micrograms/mL in PBS at pH=7.2-7.4. Examples include, butare not limited to, latanoprost free acid (0.8 mg/mL in PBS),brimonidine tartrate (0.6 mg/mL in water at pH 7.7) and brimonidine freebase (0.36 mg/mL in PBS). “High solubility” means a solubility ofgreater than or equal to 1000 micrograms/mL in PBS at pH=7.2-7.4.Examples include, but are not limited to, acetazolamide, dorzolamideHCl, timolol maleate, and ethacrynic acid sodium salt.

For ocular conditions, the active agent is suitably3-hydroxy-2,2-bis(hydroxymethyl)propyl7-((1R,2R,3R,5S)-2-((R)-3-(benzo[b]thiophen-2-yl)-3-hydroxypropyl)-3,5-dihydroxycyclopentyl)heptanoate(AR-102),7-((1R,2R,3R,5S)-2-((R)-3-(benzo[b]thiophen-2-yl)-3-hydroxypropyl)-3,5-dihydroxycyclopentyl)heptanoicacid (AR-102 free acid), dorzolamide, ethacrynic acid, latanoprost,latanoprost free acid, travoprost, travoprost free acid, bimatoprost,bimatoprost free acid, tafluprost, tafluprost free acid, dexamethasone,brimonidine, timolol, or salts thereof. Other suitable ocular activeagents are known to those of ordinary skill in the art, such as otherprostaglandins and other G-protein coupled receptor ligands,antifungals, antibiotics, enzyme inhibitors including kinase inhibitors,channel blockers, reuptake inhibitors and transporter inhibitors.

In some embodiments, the composition consists essentially of the activeagent. In other embodiments, the composition also includes excipientssuch as the carriers and other components discussed below. Thecomposition may be in the form of a single compressed pellet. In anotherembodiment, the composition may be in the form of a matrix of an activeagent and a non-water soluble polymer.

Techniques and compositions for making dosage forms useful in themethods of this invention are described in the following references:Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); andAnsel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).Examples of pharmaceutically acceptable carriers and excipients can, forexample, be found in Remington Pharmaceutical Science, 16th Ed.

Suitable carriers include, but are not limited to, phosphate bufferedsaline (PBS), isotonic water, deionized water, monofunctional alcohols,symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A andE oils, mineral oil, propylene glycol, PPG-2 myristyl propionate,dimethyl isosorbide, castor oil, combinations thereof, and the like.

The composition may also contain one or more of the following: a)diluents, b) binders, c) antioxidants, d) solvents, e) wetting agents,f) surfactants, g) emollients, h) humectants, i) thickeners, j) powders,k) sugars or sugar alcohols such as dextrans, particularly dextran 70,l) cellulose or a derivative thereof, m) a salt, n) disodium EDTA(Edetate disodium), and o) non-water soluble polymers.

Ingredient a) is a diluent. Suitable diluents for solid dosage formsinclude, but are not limited to sugars such as glucose, lactose,dextrose, and sucrose; diols such as propylene glycol; calciumcarbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol;and sorbitol. The amount of diluent in the composition is typicallyabout 0 to about 90%.

Ingredient b) is a binder. Suitable binders for solid dosage formsinclude, but are not limited to, polyethylene oxide (PEO), polyvinylpyrrolidone; magnesium aluminum silicate; starches such as corn starchand potato starch; gelatin; tragacanth; and cellulose and itsderivatives, such as sodium carboxymethylcellulose, ethyl cellulose,methylcellulose, microcrystalline cellulose, and sodiumcarboxymethylcellulose. The amount of binder in the composition istypically about 0 to about 25%.

Ingredient c) is an antioxidant such as butylated hydroxyanisole(“BHA”), butylated hydroxytoluene (“BHT”), vitamin C and vitamin E. Theamount of antioxidant in the composition is typically about 0 to about15%.

Ingredient d) is a solvent such as water, ethyl alcohol, isopropanol,castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutylether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethylformamide, and combinations thereof. The amount of ingredient d) in thecomposition is typically about 0% to about 95%. While a solvent may beused, one discovery of the present invention is that a solvent isgenerally not needed to ensure substantially linear delivery of theactive agent.

Ingredient e) is a wetting agent such as sodium lauryl sulfate,polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkylethers, sorbitan fatty acid esters, polyethylene glycols,polyoxyethylene castor oil derivatives, docusate sodium, quaternaryammonium compounds, sugar esters of fatty acids and glycerides of fattyacids.

Ingredient f) is a surfactant such as lecithin, Polysorbate 80, andsodium lauryl sulfate, and the TWEENS® from Atlas Powder Company ofWilmington, Del. Suitable surfactants include, but are not limited to,those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp.335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994,North American Edition, pp. 236-239. The amount of surfactant in thecomposition is typically about 0% to about 5%.

Ingredient g) is an emollient. Suitable emollients include, but are notlimited to, stearyl alcohol, glyceryl monoricinoleate, glycerylmonostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetylalcohol, isopropyl isostearate, stearic acid, isobutyl palmitate,isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate,decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate,di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropylstearate, butyl stearate, polyethylene glycol, triethylene glycol,lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylatedlanolin alcohols, petroleum, mineral oil, butyl myristate, isostearicacid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyllactate, decyl oleate, myristyl myristate, and combinations thereof. Theamount of emollient in the composition is typically about 0% to about50%.

Ingredient h) is a humectant. Suitable humectants include, but are notlimited to, glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate,soluble collagen, dibutyl phthalate, gelatin, and combinations thereof.The amount of humectant in the composition is typically about 0% toabout 50%.

Ingredient i) is a thickener. The amount of thickener in the compositionis typically about 0% to about 50%.

Ingredient j) is a powder. Suitable powders include, but are not limitedto, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicondioxide, tetra alkyl ammonium smectite, trialkyl aryl ammonium smectite,chemically-modified magnesium aluminum silicate, organically-modifiedmontmorillonite clay, hydrated aluminum silicate, fumed silica, sodiumcarboxymethyl cellulose, ethylene glycol monostearate, and combinationsthereof. The amount of powder in the composition is typically about 0%to about 50%.

Ingredient k) is a sugar or sugar alcohol. Suitable sugars or sugaralcohols include, but are not limited to, dextrans, dextran 70,beta-cyclodextrins, and hydroxypropyl cyclodextrins. The amount ofsugars or sugar alcohols in the composition is typically about 0% toabout 60%.

Ingredient l) is a cellulose derivative. Suitable cellulose derivativesinclude, but are not limited to, sodium carboxymethylcellulose,ethylcellulose, methylcellulose, and hydroxypropyl-methylcellulose,particularly, hydroxypropylmethylcellulose.

Ingredient m) is a salt. Suitable salts include, but are not limited to,mono-, di- and trisodium phosphate, sodium chloride, potassium chloride,and combinations thereof.

Ingredient n) is disodium EDTA (Edetate disodium). The amount ofdisodium EDTA in the composition is typically about 0% to about 1%.

Ingredient o) is a non-water soluble polymer. The non-water solublepolymer may be selected from ethylene vinyl acetate (EVA), siliconrubber polymers, polydimethylsiloxane (PDMS), polyurethane (PU),polyesterurethanes, polyetherurethanes, polyolefins, polyethylenes (PE),low density polyethylene (LDPE), polypropylene (PP),polyetheretherketone (PEEK), polysulfone (PSF), polyphenylsulfone,polyacetals, polymethyl methacrylate (PMMA), polybutylmethacrylate,plasticized polyethyleneterephthalate, polyisoprene, polyisobutylene,silicon-carbon copolymers, natural rubber, plasticized soft nylon,polytetrafluoroethylene (PTFE), or combinations thereof. Suitably, thenon-water soluble polymer is EVA. The vinyl acetate content may be fromabout 9% to about 50% by weight (EVA-9-50). In one embodiment, the vinylacetate content is about 40% by weight (EVA-40). Other suitablenon-water soluble polymers are known to those of ordinary skill in theart.

The drug delivery devices of the present invention may be included inkits, which include the drug delivery devices and information,instructions, or both for use of the kit to provide treatment formedical conditions in mammals (particularly humans). The information andinstructions may be in the form of words, pictures, or both, and thelike.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention are to be construed to cover boththe singular and the plural, unless otherwise indicated herein orclearly contradicted by context. The terms “comprising,” “having,”“including,” and “containing” are to be construed as open-ended terms(i.e., meaning “including, but not limited to,”) unless otherwise noted.Recitation of ranges of values herein are merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range, unless otherwise indicated herein, and eachseparate value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein, isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention unless otherwise claimed. Nolanguage in the specification should be construed as indicating anynonclaimed element as essential to the practice of the invention.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention.Variations of those preferred embodiments may become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

EXAMPLES

The invention will be further explained by the following illustrativeexamples that are intended to be non-limiting.

Procedures for preparation of the drug delivery devices are described inthe following examples. All temperatures are given in degreesCentigrade. Reagents were purchased from commercial sources (given) orprepared following literature procedures.

Example 1: Drug Delivery Device Containing Dorzolamide HCl (a HighSolubility Drug) Parameters Tested Thickness of Permeable EVA Film:40-250 Micrometers Elution Rate: 0.1-2 Micrograms/Hr

30 mg of dorzolamide HCl (which has high solubility) was compressed at1000 psi to form a compressed drug pellet with a diameter of 5 mm and athickness of 1 mm. Next, 15 mg of EVA-25 (vinyl acetate content of 25%;Sigma Chemical Company, St. Louis, Mo.) was loaded into a custom-madedie set and heated to 100° C. for 1 minute. The polymer was compressedat 100 psi and allowed to cool to room temperature. When prepared inthis manner, this EVA-25 polymer membrane is impermeable to water. Themolded polymer cup was removed from the die set and the compressed drugpellet was loaded into the cup with the top side uncovered.

EVA-40 (Sigma Chemical Company, St. Louis, Mo.) was loaded into a filmmaker (International Crystal Laboratory) with a 150-micrometer spacerand heated to 75° C. for 4 minutes. The polymer was compressed at 1500psi for 1 minute and allowed to cool to room temperature. The polymermembrane thus created with a thickness of 150 micrometers was removedfrom the base and cut into a discshaped membrane with a diameter of 6 mmusing a biopsy punch. This polymer membrane is permeable to water whenprepared in this manner. The disc-shaped, permeable membrane was placedon the exposed side of the drug pellet in contact with the EVA-25 “cup”,and the two polymers were heat-sealed at 90° C. using a custom-made dieset and allowed to cool to room temperature.

In summary, this drug delivery device was composed of a 30 mg core ofdorzolamide HCl, the top and sides were composed of the impermeableEVA-25 polymer membrane, and the bottom of the drug delivery device wasa 150 micrometer rate-limiting water-permeable membrane composed ofEVA-40. The average elution rate in this particular design was 0.66±0.05micrograms/hr (R2=0.9999) (FIG. 81).

Example 2: Drug Delivery Device Containing Ethacrynic Acid Sodium Salt(a High Solubility Drug) Parameters Tested Thickness of EVA Film:100-500 Micrometers Elution Rate: 5-50 Micrograms/Hr

30 mg of ethacrynic acid sodium salt (Sigma Chemical Company, St. Louis,Mo.) (which has high solubility), was compressed at 1000 psi to form acompressed drug pellet with a diameter of 5 mm and a thickness of 1 mm.15 mg of EVA-25 (Sigma Chemical Company, St. Louis, Mo.) was loaded intoa custom-made die set and heated to 100° C. for 1 minute. The polymerwas compressed at 100 psi and allowed to cool to room temperature. Whenprepared in this manner, this polymer membrane was impermeable to water.The molded polymer cup was removed from the die set and the compresseddrug pellet was loaded into the cup with the top side uncovered.

EVA-40 (Sigma Chemical Company, St. Louis, Mo.) was loaded into a filmmaker (International Crystal Laboratory) with a 25-micrometer spacer andheated to 75° C. for 4 minutes. The polymer was compressed at 200 psifor 1 minute and allowed to cool to room temperature. The thus createdpolymer membrane with a thickness of 75 micrometers was removed from thebase and cut into a disc-shaped membrane with a diameter of 6 mm using abiopsy punch. This polymer membrane was permeable to water when preparedin this manner. The disc-shaped, permeable membrane was placed on theexposed side of the drug pellet in contact with the EVA-25 “cup”, andthe two polymers were heat-sealed at 90° C. using a custom-made die setand allowed to cool to room temperature.

In summary, this drug delivery device was composed of a 30 mg core ofethacrynic acid sodium salt, the top and sides were composed of animpermeable EVA-25 polymer membrane, and the bottom of the drug deliverydevice was a 75 micrometer rate-limiting water-permeable membranecomposed of EVA-40. The elution rate in this particular design was 27micrograms/hr with a zero-order release profile for up to 90% of thecontained agent (R2=0.9997) (FIG. 82).

Ethacrynic acid sodium salt drug delivery devices falling within theabove parameters with an elution rate of approximately 20 micrograms/hrwere inserted episclerally in the right eye of Dutch-belted rabbits andthe contralateral eye was used as an untreated control. The intraocularpressure was measured at regular intervals. As shown in FIG. 83, thedevices provided a sustained IOP-lowering effect for approximately 30days with >90% elution of the agent achieved.

Example 3: Drug Delivery Device Containing AR-102 Free Acid (aModerately Soluble Drug) Parameters Tested Thickness of EVA Film:120-250 Micrometers Elution Rate: 0.04-0.7 Micrograms/Hr

4 mg of AR-102 free acid (which has moderate solubility) was compressedat 1000 psi to form a compressed drug pellet with a diameter of 3 mm anda thickness of 1 mm. 8 mg of EVA-25 (Sigma Chemical Company, St. Louis,Mo.) was loaded into a custom-made die set and heated to 100° C. for 1minute. The polymer was compressed at 100 psi and allowed to cool toroom temperature. This was the impermeable polymer. The molded polymercup was removed from the die set and the compressed drug pellet wasloaded into the cup with the top side uncovered.

EVA-40 (Sigma Chemical Company, St. Louis, Mo.) was loaded into a filmmaker (International Crystal Laboratory) with a 200-micrometer spacerand heated to 75° C. for 4 minutes. The polymer was compressed at 200psi for 1 minute and allowed to cool to room temperature. The polymermembrane with a thickness of 250 micrometers was removed from the baseand cut into a disc-shaped membrane with a diameter of 4 mm using abiopsy punch. This polymer membrane was permeable to water when preparedin this manner. The disc-shaped, permeable membrane was placed on theexposed side of the drug pellet in contact with the EVA-25 “cup”, andthe two polymers were heat-sealed at 90° C. using a custom-made die setand allowed to cool to room temperature.

In summary, this device was composed of a 4 mg core of AR-102 free acid.The impermeable polymer was EVA-25. The rate-limiting water-permeablepolymer was EVA-40, and the thickness of the water-permeable membranewas 250 micrometers. The elution rate in this particular design was 0.16micrograms/hr (R2=0.9998) (FIG. 84).

AR-102 free acid drug delivery devices falling within the aboveparameters with an elution rate of approximately 0.03 micrograms/hr wereinserted episclerally in the right eye of Dutch-belted rabbits and thecontralateral eye was used as an untreated control. The intraocularpressure was measured at regular intervals. As shown in FIG. 85, thedevices provided a sustained TOP-lowering effect with a theoreticalduration in vivo of approximately 7 years.

Example 4: Drug Delivery Device Containing Latanoprost Arginine Salt (aModerately Soluble Drug) Parameters Tested Thickness of EVA Film: 40-300Micrometers Elution Rate: 0.04-5 Micrograms/Hr

4 mg of latanoprost arginine salt (which has moderate solubility) wascompressed at 1000 psi to form a compressed drug pellet with a diameterof 3 mm and a thickness of 1 mm. 8 mg of EVA-25 (Sigma Chemical Company,St. Louis, Mo.) was loaded into a custom-made die set and heated to 100°C. for 1 minute. The polymer was compressed at 100 psi and allowed tocool to room temperature. This was the impermeable polymer. The moldedpolymer cup was removed from the die set and the compressed drug pelletwas loaded into the cup with the top side uncovered.

EVA-40 (Sigma Chemical Company, St. Louis, Mo.) was loaded into a filmmaker (International Crystal Laboratory) with a 150-micrometer spacerand heated to 75° C. for 4 minutes. The polymer was compressed at 400psi for 1 minute and allowed to cool to room temperature. The polymermembrane with a thickness of 160 micrometers was removed from the baseand cut into a disc-shaped membrane with a diameter of 4 mm using abiopsy punch. This polymer membrane was permeable to water when preparedin this manner. The disc-shaped, permeable membrane was placed on theexposed side of the drug pellet in contact with the EVA-25 “cup”, andthe two polymers were heat-sealed at 90° C. using a custom-made die setand allowed to cool to room temperature.

In summary, this device was composed of a 4 mg core of latanoprostarginine salt. The impermeable polymer was EVA-25. The rate-limitingwaterpermeable polymer was EVA-40, and the thickness of thewater-permeable membrane was 160 micrometers. The elution rate in thisparticular design was approximately 0.01 micrograms/hr (R2=0.9977) (FIG.86).

A latanoprost free acid arginine salt drug delivery device fallingwithin the above parameters with an elution rate of approximately 0.01micrograms/hr was inserted episclerally in the right eye of Dutch-beltedrabbits and the contralateral eye was used as an untreated control. Theintraocular pressure was measured at regular intervals. As shown in FIG.87, the device provided a sustained IOP-lowering effect forapproximately 30 days with a theoretical duration in vivo ofapproximately 30 years.

Example 5: Drug Delivery Device Containing Dexamethasone (a LowSolubility Drug) Parameters Tested Thickness of EVA Film: 40-150Micrometers Elution Rate: 0.1-3 Micrograms/Hr

30 mg of dexamethasone (which has low solubility) was compressed at 1000psi to form a compressed drug pellet with a diameter of 5 mm and athickness of 1 mm. 15 mg of EVA-25 (Sigma Chemical Company, St. Louis,Mo.) was loaded into a custom-made die set and heated to 100° C. for 1minute. The polymer was compressed at 100 psi and allowed to cool toroom temperature. This was the impermeable polymer. The molded polymercup was removed from the die set and the compressed drug pellet wasloaded into the cup with the top side uncovered.

EVA-40 (Sigma Chemical Company, St. Louis, Mo.) was loaded into a filmmaker (International Crystal Laboratory) with a 50-micrometer spacer andheated to 75° C. for 4 minutes. The polymer was compressed at 200 psifor 1 minute and allowed to cool to room temperature. The polymermembrane with a thickness of 75 micrometers was removed from the baseand cut into a disc-shaped membrane with a diameter of 6 mm using abiopsy punch. This polymer membrane is permeable to water when preparedin this manner. The disc-shaped, permeable membrane was placed on theexposed side of the drug pellet, and the two polymers were heatsealed at90° C. using a custom-made die set and allowed to cool to roomtemperature.

In summary, this device was composed of a 30 mg core of dexamethasone.The impermeable polymer was EVA-25. The rate-limiting waterpermeablepolymer was EVA-40, and the thickness of the water-permeable membranewas 75 micrometers. The elution rate in this particular design was 0.25micrograms/hr (R2=0.9999) (FIG. 88).

Example 6: Ethylene Vinyl Acetate/Dextran Film Standard Methods forMaking EVA/Dextran Film

Dextran with an average molecular weight of 5,000-670,000 Daltons(Fluka) was desiccated under vacuum overnight to purge excess moisture.EVA pellets with selected vinyl acetate ratios from 0 to 40% were groundinto fine pieces to increase surface area. Dextran and EVA-O-40 werethen measured out at a selected weight ratio in a sealed glass vial.Dichloromethane was incrementally added to the dextran/EVA mixture andthe mixture was vigorously shaken to prevent clumping of dextran. Themixture was then gently heated to 50° C. and shaken in quick successionto aid EVA-25 dissolution. The mixture was then placed in an ultrasonicbath for 2 minutes. The mixture was allowed to cool to room temperatureand inspected for undesirable air bubble formation.

A glass plate or silicon wafer was used as a casting substrate for theevaporative casting of the film. The mixture was uncapped and quicklydecanted onto the substrate. Typical drying time was at least 4 hoursunder low humidity conditions to limit moisture uptake by thehygroscopic dextran. The cast film was then placed in a negativepressure rated flask and the atmosphere was flushed with high purityArgon gas. Air was then evacuated under a high vacuum overnight. Thedried film was grounded into fine powder, and a dextran/EVA film withdesired thickness was made by heat compression in a film maker. Adigital micrometer was used to verify the final film thickness.

Example 7: Drug Delivery Device Containing Dexamethasone SodiumPhosphate (a High Solubility Drug) Parameters Tested Dextran MolecularWeight: 5-12 kDa Weight Ratio of Dextran/EVA Film: 1:20 to 1:4 Thicknessof Dextran/EVA Film: 40-150 Micrometers Elution Rate: 2-200Micrograms/Hr

30 mg of dexamethasone sodium phosphate (which has high solubility) wascompressed at 1000 psi to form a compressed drug pellet with a diameterof 5 mm and a thickness of 1 mm. 15 mg of EVA-25 (Sigma ChemicalCompany, St. Louis, Mo.) was loaded into a custom-made die set andheated to 100° C. for 1 minute. The polymer was compressed at 100 psiand allowed to cool to room temperature. This was the impermeablepolymer. The molded polymer cup was removed from the die set and thecompressed drug pellet was loaded into the cup with the top sideuncovered.

A mixture of EVA-25 (Sigma Chemical Company, St. Louis, Mo.) and dextranwith an average molecular weight of 5 kDa was loaded into a film maker(International Crystal Laboratory) with a 100-micrometer spacer andheated to 100° C. for 4 minutes. The weight ratio of the dextran/EVAfilm was 1:19. The polymer was compressed at 200 psi for 1 minute andallowed to cool to room temperature. The polymer membrane with athickness of 120 micrometers was removed from the base and cut into adisc-shaped membrane with a diameter of 6 mm using a biopsy punch. Thiswas the partially-bioerodible membrane. The disc-shape,partially-bioerodible membrane was placed on the exposed side of thedrug pellet in contact with the EVA-25 “cup”, and the two polymers wereheat-sealed at 90° C. using a custom-made die set and allowed to cool toroom temperature.

In summary, this device was composed of a 30 mg core of dexamethasonesodium phosphate. The impermeable polymer was EVA-25. Thepartially-bioerodible membrane was dextran with an average weightmolecular of 5 kDa and EVA-25 at a weight ratio of 1:19, and thethickness of the partially bioerodible membrane was 120 micrometers. Theelution rate in this particular design was approximately 14micrograms/hr (R2=0.9954) (FIG. 89).

Example 8: Drug Delivery Device Containing Brimonidine Free Base (a LowSolubility Drug) Parameters Tested Dextran Molecular Weight: 12-670 kDaWeight Ratio of Dextran/EVA Film: 1:4 to 1:3 Thickness of Dextran/EVAFilm: 40-150 Micrometers Elution Rate: 0.05-4 Micrograms/Hr

20 mg of brimonidine free base (which has low solubility) was compressedat 1000 psi to form a compressed drug pellet with a diameter of 5 mm anda thickness of 1 mm. 15 mg of EVA-25 (Sigma Chemical Company, St. Louis,Mo.) was loaded into a custom-made die set and heated to 100° C. for 1minute. The polymer was compressed at 100 psi and allowed to cool toroom temperature. This was the impermeable polymer. The molded polymercup was removed from the die set and the compressed drug pellet wasloaded into the cup with the top side uncovered.

A mixture of EVA-25 (Sigma Chemical Company, St. Louis, Mo.) and dextranwith an average molecular weight of 270 kDa was loaded into a film maker(International Crystal Laboratory) with a 50-micrometer spacer andheated to 75° C. for 4 minutes. The weight ratio of the dextran/EVA filmwas 1:4. The polymer was compressed at 400 psi for 1 minute and allowedto cool to room temperature. The polymer membrane which had a thicknessof 65 micrometers was removed from the base and cut into a disc-shapedmembrane with a diameter of 6 mm using a biopsy punch. This was thepartially-bioerodible membrane. The disc-shaped, partially bioerodiblemembrane was placed on the exposed side of the drug pellet in contactwith the EVA-25 “cup”, and the two polymers were heat-sealed at 90° C.using a custom-made die set and allowed to cool to room temperature.

In summary, this device was composed of a 20 mg core of brimonidine freebase. The impermeable polymer was EVA-25. The partially-bioerodiblemembrane was synthesized using dextran with an average molecular weightof 270 kDa and EVA-25 at a weight ratio of 1:4, and the thickness of thepartially-bioerodible membrane was 65 micrometers. The elution rate inthis particular design was 0.7 micrograms/hr (R2=0.9997) (FIG. 90).

Brimonidine free base drug delivery devices falling within the aboveparameters using a similar design with elution rates of 0.7-2.5micrograms/hr were inserted below the sclera in the right eye ofDutch-belted rabbits and the contralateral eye was used as an untreatedcontrol. The intraocular pressure was measured at regular intervals. Asshown in FIG. 91, the device provided a sustained IOP-lowering effectfor approximately 38 days with an expected duration in vivo of at least7 months.

Example 9: Drug Delivery Device Containing Brimonidine D-Tartrate Salt(a High Solubility Drug) Parameters Tested Dextran Molecular Weight:5-270 kDa Weight Ratio of Dextran/EVA Film: 1:20 to 1:4 Thickness ofDextran/EVA Film: 95-150 Micrometers Elution Rate: 0.3-60 Micrograms/Hr

30 mg of brimonidine D-tartrate salt (which has high solubility) wascompressed at 1000 psi to form a compressed drug pellet with a diameterof 5 mm and a thickness of 1 mm. 15 mg of EVA-25 (Sigma ChemicalCompany, St. Louis, Mo.) was loaded into a custom-made die set andheated to 100° C. for 1 minute. The polymer was compressed at 100 psiand allowed to cool to room temperature. This was the impermeablepolymer. The molded polymer cup was removed from the die set and thecompressed drug pellet was loaded into the cup with the top sideuncovered.

A mixture of EVA-25 (Sigma Chemical Company, St. Louis, Mo.) and dextranwith an average molecular weight of 270 kDa was loaded into a film maker(International Crystal Laboratory) with a 100-micrometer spacer andheated to 100° C. for 4 minutes. The weight ratio of the dextran/EVAfilm was 1:4. The polymer was compressed at 200 psi for 1 minute andallowed to cool to room temperature. The polymer membrane which had athickness of 125 micrometers was removed from the base and cut into adisc-shaped membrane with a diameter of 6 mm using a biopsy punch. Thiswas the partially-bioerodible membrane. The disc-shaped, partiallybioerodible membrane was placed on the exposed side of the drug pelletin contact with the EVA-25 “cup”, and the two polymers were heat-sealedat 90° C. using a custom-made die set and allowed to cool to roomtemperature.

In summary, this device was composed of a 30 mg core of brimonidineD-tartrate salt. The impermeable polymer was EVA-25. Thepartially-bioerodible membrane was dextran with an average molecularweight of 270 kDa and EVA-25 at a weight ratio of 1:4, and the thicknessof the partially-bioerodible membrane was 125 micrometers. The elutionrate in this particular design was approximately 34 micrograms/hr with azero-order release profile for up to 95% (R2=0.9948) (FIG. 92).

Example 10: Drug Delivery Device Containing Timolol Maleate Salt (a HighSolubility Drug) Parameters Tested Dextran Molecular Weight: 5-670 kDaWeight Ratio of Dextran/EVA Film: 1:20 to 1:3 Thickness of Dextran/EVAFilm: 40-150 Micrometers Elution Rate: 1-50 Micrograms/Hr

30 mg of timolol maleate (which has high solubility) was compressed at1000 psi to form a compressed drug pellet with a diameter of 5 mm and athickness of 1 mm. 15 mg of EVA-25 (Sigma Chemical Company, St. Louis,Mo.) was loaded into a custom-made die set and heated to 100° C. for 1minute. The polymer was compressed at 100 psi and allowed to cool toroom temperature. This was the impermeable polymer. The molded polymercup was removed from the die set and the compressed drug pellet wasloaded into the cup with the top side uncovered.

A mixture of EVA-25 (Sigma Chemical Company, St. Louis, Mo.) and dextranwith an average molecular weight of 5 kDa was loaded into a film maker(International Crystal Laboratory) with a 100-micrometer spacer andheated to 75° C. for 4 minutes. The weight ratio of the dextran/EVA filmwas 1:9. The polymer was compressed at 1500 psi for 1 minute and allowedto cool to room temperature. The polymer membrane which had a thicknessof 100 micrometers was removed from the base and cut into a disc-shapedmembrane with a diameter of 6 mm using a biopsy punch. This was thepartially-bioerodible membrane. The disc-shape, partially bioerodiblemembrane was placed on the exposed side of the drug pellet in contactwith the EVA-25 “cup”, and the two polymers were heat-sealed at 90° C.using a custom-made die set and allowed to cool to room temperature.

In summary, this device was composed of a 30 mg core of timolol maleatesalt. The impermeable polymer was EVA-25. The partially-bioerodiblemembrane was dextran with an average molecular weight of 5 kDa andEVA-25 at a weight ratio of 1:9, and the thickness of thepartially-bioerodible membrane was 100 micrometers. The elution rate inthis particular design was approximately 15 micrograms/hr with azero-order release profile for up to 90% of the enclosed agent(R2=0.9986) (FIG. 93).

Timolol maleate salt drug delivery devices falling within the aboveparameters with elution rates of about 12 to 18 micrograms/hr wereinserted below the sclera in the right eye of Dutch-belted rabbits andthe contralateral eye was used as an untreated control. The intraocularpressure was measured at regular intervals. As shown in FIG. 94, thedevice provided a sustained IOP-lowering effect for approximately 90days with complete elution achieved.

Example 11: Drug Delivery Device Containing Albumin (a High MolecularWeight, High Solubility Compound) Parameters Tested Dextran MolecularWeight: 270-670 kDa Weight Ratio of Dextran/EVA Film: 1:20 to 1:3Thickness of Dextran/EVA Film: 40-150 Micrometers

30 mg of albumin (average molecular weight of approximately 67 kDa) thathad been labeled with fluorescein isothiocyanate (BSA-FITC, Fluka)(which has high solubility) was mixed with unlabeled albumin at weightratio of 1:9 and compressed at 1000 psi to form a compressed drug pelletwith a diameter of 5 mm and a thickness of 1 mm. 15 mg of EVA-25 (SigmaChemical Company, St. Louis, Mo.) was loaded into a custom-made die setand heated to 100° C. for 1 minute. The polymer was compressed at 100psi and allowed to cool to room temperature. This was the impermeablepolymer. The molded polymer cup was removed from the die set and thecompressed drug pellet was loaded into the cup with the top sideuncovered.

A mixture of EVA-25 (Sigma Chemical Company, St. Louis, Mo.) and dextranwith an average molecular weight of 670 kDa was loaded into a film maker(International Crystal Laboratory) with a 50-micrometer spacer andheated to 100° C. for 4 minutes. The weight ratio of dextran/EVA filmwas 1:4. The polymer was compressed at 150 psi for 1 minute and allowedto cool to room temperature. The polymer membrane which had a thicknessof 85 micrometers was removed from the base and cut into a disc-shapedmembrane with a diameter of 6 mm using a biopsy punch. This was thepartially-bioerodible membrane. The disc-shaped, partially-bioerodiblemembrane was placed on the exposed side of the drug pellet in contactwith the EVA-25 “cup”, and the two polymers were heat-sealed at 90° C.using a custom-made die set and allowed to cool to room temperature.

In summary, this device was composed of a 30 mg core of albumin with 10%of the core consisting of FITC-labeled albumin. The impermeable polymerwas EVA-25. The partially-bioerodible membrane was dextran with anaverage molecular weight of 670 kDa and EVA-25 at a weight ratio of 1:4,and the thickness of the partially-bioerodible membrane was 85micrometers. The data showed that albumin was released from thepermeable polymer at a controlled rate.

Example 12: General Methods of In Vitro Elution Rate Determination

A drug delivery device, containing a known active agent of interest, isplaced in a 20-mL Class A clear borosilicate glass vial with PTFEthreaded lid. To the vial is then added 10 mL of sterile 1×phosphate-buffered saline (PBS) without calcium and magnesium salts(Mediatech). The 20-mL glass vial is placed onto a tight fitting polymerrack. The polymer rack is then placed on an adjustable orbital platformshaker set to 60 Hz with infinite duration in a 37° C. incubator. Atpredetermined time points, 1-2 ml of the incubated solution istransferred from the vial to a sampling vial, and the rest of thesolution is aspirated. The predetermined time intervals are usually 48or 72 hours, and are subject to change based on the target elution rateand the maximum solubility of the active agent in PBS. 10 mL of freshPBS is added to the 20-mL vial, and the vial is placed back to theincubator. In general, the concentration of active agent in solution ismaintained at less than 10% of its maximum solubility in PBS to ensurethe near-sink conditions.

The concentration of the solution in the sampling vial is determinedusing a standard curve obtained from several (usually more than 8)different known concentrations of the same active agent. The totalamount of active agent eluted is determined from the original volume ofthe incubating solution and the elution rate is calculated based on theincubation time.

Example 13: Drug Delivery Device Containing Bimatoprost (a LowSolubility Drug) Suggested Parameters Thickness of EVA Film: 40-500Micrometers Elution Rate: 0.005-0.3 Micrograms/Hr Preferred ElutionRate: 0.002-0.1 Micrograms/Hr

4 mg of bimatoprost (which has low solubility) is compressed at 1000 psito form a compressed drug pellet with a diameter of 3 mm and a thicknessof 1 mm. 8 mg of EVA-25 (Sigma) is loaded into a custom-made die set andheated to 100° C. for 1 minute. The polymer is compressed at 100 psi andallowed to cool to room temperature. This is the impermeable polymer.The molded polymer cup is removed from the die set and the compresseddrug pellet is loaded into the cup with the top side uncovered.

EVA-40 is loaded into a film maker with a suitable spacer and heated to75° C. for 4 minutes. The polymer is compressed at constant pressure for1 minute and allowed to cool to room temperature. The polymer membranewith a thickness of 40-500 micrometers is removed from the base and cutinto a disc-shaped membrane with a diameter of 4 mm using a biopsypunch. This polymer membrane is permeable to water when prepared in thismanner. The disc-shaped, permeable membrane is placed on the exposedside of the drug pellet in contact with the EVA-25 “cup”, and the twopolymers are heat-sealed at 90° C. using a custom-made die set andallowed to cool to room temperature.

In summary, this device is composed of a 4 mg core of bimatoprost. Thetop and sides are composed of an impermeable EVA-25 polymer membrane,and the bottom of the drug delivery device is a 40-500 micrometerpermeable membrane composed of EVA-40. The elution rate in this designcan be adjusted to the desired elution rate by changing the thickness ofthe permeable polymer.

Example 14: Drug Delivery Device Containing Latanoprost Isopropyl Ester(a Low Solubility Drug) Suggested Parameters Thickness of EVA Film:300-1000 Micrometers Elution Rate: 0.005-0.3 Micrograms/Hr PreferredElution Rate: 0.001-0.05 Micrograms/Hr

8 mg of EVA-25 is loaded into a custom-made die set and heated to 100°C. for 1 minute. The polymer is compressed at 100 psi and allowed tocool to room temperature. This is the impermeable polymer. The moldedpolymer cup is removed from the die set and 4 mg of latanoprostisopropyl ester (which has low solubility) is loaded into the EVA-25cup.

EVA-40 is loaded into a film maker with a suitable spacer and heated to75° C. for 4 minutes. The polymer is compressed at constant pressure for1 minute and allowed to cool to room temperature. The polymer membranewith a thickness of 300-800 micrometers is removed from the base and cutinto a disc-shaped membrane with a diameter of 4 mm using a biopsypunch. This polymer membrane is permeable to water when prepared in thismanner. The disc-shaped, permeable membrane is placed on the exposedside of the drug pellet in contact with the EVA-25 “cup,” and the twopolymers are heat-sealed at 90° C. using a custom-made die set andallowed to cool to room temperature.

In summary, this device is composed of a 4 mg core of latanoprostisopropyl ester. The top and sides are composed of an impermeable EVA-25polymer membrane, and the bottom of the drug delivery device is a 40-500micrometer permeable membrane composed of EVA-40. The elution rate inthis design can be adjusted to desired elution rate by changing thethickness of the permeable polymer.

Example 15: Drug Delivery Device Containing Travoprost Isopropyl Ester(a Low Solubility Drug) Suggested Parameters Thickness of EVA Film:300-750 Micrometers Elution Rate: 0.001-0.04 Micrograms/Hr PreferredElution Rate: 0.001-0.02 Micrograms/Hr

8 mg of EVA-25 is loaded into a custom-made die set and heated to 100°C. for 1 minute. The polymer is compressed at 100 psi and allowed tocool to room temperature. This is the impermeable polymer. The moldedpolymer cup is removed from the die set and 4 mg of travoprost isopropylester (which has low solubility) is loaded into the EVA-25 cup.

EVA-40 is loaded into a film maker (International Crystal Laboratory)with a suitable spacer and heated to 75° C. for 4 minutes. The polymeris compressed at constant pressure for 1 minute and allowed to cool toroom temperature. The polymer membrane with a thickness of 300-800micrometers is removed from the base and cut into a disc-shaped membranewith a diameter of 4 mm using a biopsy punch. This polymer membrane ispermeable to water when prepared in this manner. The disc-shaped,permeable membrane is placed on the exposed side of the drug pellet incontact with the EVA-25 “cup,” and the two polymers are heat-sealed at90° C. using a custom-made die set and allowed to cool to roomtemperature.

In summary, this device is composed of a 4 mg core of travoprostisopropyl ester. The top and sides are composed of an impermeable EVA-25polymer membrane, and the bottom of the drug delivery device is a 40-500micrometer permeable membrane composed of EVA-40.

Example 16: Drug Delivery Device Containing Non-SteroidalAnti-Inflammatory Drugs

A drug delivery device of the invention can be designed to release aselected active agent at a predetermined rate using the flowcharts andtable in FIGS. 95-97. Suitably, one would start with EVA-40 as the waterpermeable membrane and EVA-25 as the water impermeable membrane, orusing partially-bioerodible membranes if the active agent may notrelease at the predetermined rate. For those skilled in the art, thecomposition and thickness of the membrane can readily be identifiedusing similar experimental procedures illustrated above.

Example 17: Drug Delivery Device Containing Latanoprost Arginine Salt (aModerately Soluble Drug) Parameters Tested Thickness of EVA Film: 40-300Micrometers Elution Rate: 0.00025-0.025 Micrograms/Hr Preferred ElutionRate: 0.00025-0.0075 Micrograms/Hr

The drug core film was prepared using a solvent casting technique. 50 mgof latanoprost arginine salt and 200 mg of EVA-40 (Sigma ChemicalCompany, St. Louis, Mo.) were dissolved in 3 mL of dichloromethane(DCM). The polymer solution was cast on a custom-madepolydimethylsiloxane (PDMS) substrate, and the cast film was dried atambient temperature in a fume hood for 2 days. The drug core film with athickness of 100-125 micrometers was removed from the base and cut intodisc-shaped pieces with a diameter of 2 mm using a biopsy punch.

EVA-25 (Sigma Chemical Company, St. Louis, Mo.) was loaded into a filmmaker (International Crystal Laboratory) with a 100-micrometer spacerand heated to 95° C. for 4 minutes. The polymer was compressed at 400psi for 1 minute and allowed to cool to room temperature. The polymermembrane with a thickness of 125 micrometers was removed from the baseand cut into disc-shaped membranes with a diameter of 4 mm using abiopsy punch. This polymer membrane was permeable to water when preparedin this manner. Some of these 4-mm membranes were subsequentlymanufactured to donut-shaped rings with an outer diameter of 4 mm and aninner diameter of 2 mm. This polymer membrane is the “spacer ring”(FIGS. 46-65). A 2-mm drug core film containing latanoprost argininesalt and EVA-40 was then inserted into the void of a spacer ring, andboth sides of the composite film were covered by a 4-mm EVA-25 film (thepermeable membrane). The four-piece assembly (2 EVA-25 permeablemembranes, 1 spacer ring, and 1 drug core film) was then heat-sealed at90° C. using a custom-made die set and allowed to cool to roomtemperature.

In summary, this device was composed of a drug core film of 20%latanoprost arginine salt and 80% of EVA-40. The rate-limiting waterpermeable polymer was EVA-25, and the thickness of the water-permeablemembranes was 125 micrometers. The elution rate in this particulardesign was approximately 0.005 micrograms/hr.

Example 18: Drug Delivery Device Containing Bimatoprost (a LowSolubility Drug) Suggested Parameters Thickness of EVA Film: 40-300Micrometers Elution Rate: 0.003-0.3 Micrograms/Hr Preferred ElutionRate: 0.002-0.1 Micrograms/Hr

The drug core film was prepared using a solvent casting technique. 50 mgof bimatoprost and 200 mg of EVA-40 (Sigma Chemical Company, St. Louis,Mo.) were dissolved in 3 mL of dichloromethane (DCM). The polymersolution was cast on a custom-made polydimethylsiloxane (PDMS)substrate, and the cast film was dried at ambient temperature in a fumehood for 2 days. The drug core film with a thickness of 100-125micrometers was removed from the base and cut into disc-shaped pieceswith a diameter of 2 mm using a biopsy punch.

EVA-25 (Sigma Chemical Company, St. Louis, Mo.) was loaded into a filmmaker (International Crystal Laboratory) with a 100-micrometer spacerand heated to 95° C. for 4 minutes. The polymer was compressed at 400psi for 1 minute and allowed to cool to room temperature. The polymermembrane with a thickness of 125 micrometers was removed from the baseand cut into disc-shaped membranes with a diameter of 4 mm using abiopsy punch. This polymer membrane was permeable to water when preparedin this manner. Some of these 4-mm membranes were subsequentlymanufactured to donut-shaped rings with an outer diameter of 4 mm and aninner diameter of 2 mm. This polymer membrane is the “spacer ring”(FIGS. 46-65). A 2-mm drug core film containing bimatoprost and EVA-40was then inserted into the void of a spacer ring, and both sides of thecomposite film were covered by a 4-mm EVA-25 film (the permeablemembrane). The four-piece assembly (2 EVA-25 permeable membranes, 1spacer ring, and 1 drug core film) was then heat-sealed at 90° C. usinga custom-made die set and allowed to cool to room temperature.

In summary, this device was composed of a drug core film of 20%bimatoprost and 80% of EVA-40. The rate-limiting water permeable polymerwas EVA-25, and the thickness of the water-permeable membranes was 125micrometers. The elution rate in this particular design wasapproximately 0.015-0.020 micrograms/hr.

Example 19: Drug Delivery Device Containing Y-39983 Free Base (aModerately Soluble Drug) Parameters Tested Thickness of EVA Film: 40-300Micrometers Elution Rate: 0.01-1.0 Micrograms/Hr Preferred Elution Rate:0.04-0.6 Micrograms/Hr

The drug core film was prepared using a solvent casting technique. 100mg of Y-39983 free base and 100 mg of EVA-40 (Sigma Chemical Company,St. Louis, Mo.) were dissolved in 3 mL of dichloromethane (DCM). Thepolymer solution was cast on a custom-made polydimethylsiloxane (PDMS)substrate, and the cast film was dried at ambient temperature in a fumehood for 2 days. The drug core film with a thickness of 75-90micrometers was removed from the base and cut into disc-shaped pieceswith a diameter of 2.5 mm using a biopsy punch.

EVA-40 (Sigma Chemical Company, St. Louis, Mo.) was loaded into a filmmaker (International Crystal Laboratory) with a 50-micrometer spacer andheated to 75° C. for 4 minutes. The polymer was compressed at 300 psifor 1 minute and allowed to cool to room temperature. The polymermembrane with a thickness of 90 micrometers was removed from the baseand cut into disc-shaped membranes with a diameter of 4 mm using abiopsy punch. This polymer membrane was permeable to water when preparedin this manner. Some of these 4-mm membranes were subsequentlymanufactured to donut-shaped rings with an outer diameter of 4 mm and aninner diameter of 2.5 mm. This polymer membrane is the “spacer ring”(FIGS. 46-65). A 2.5-mm drug core film containing Y-39983 free base andEVA-40 was then inserted into the void of a spacer ring, and both sidesof the composite film were covered by a 4-mm EVA-40 film (the permeablemembrane). The four-piece assembly (2 EVA-40 permeable membranes, 1spacer ring, and 1 drug core film) was then heat-sealed at 75° C. usinga custom-made die set and allowed to cool to room temperature.

In summary, this device was composed of a drug core film of 50% Y-39983free base and 50% EVA-40. The rate-limiting water permeable polymer wasEVA-40, and the thickness of the water-permeable membranes was 90micrometers. The elution rate in this particular design wasapproximately 0.015-0.020 micrograms/hr.

Example 20: Drug Delivery Device Containing Latanoprost Arginine Salt (aModerately Soluble Drug) Parameters Tested Thickness of EVA Film: 40-300Micrometers Elution Rate: 0.0005-0.03 Micrograms/Hr Preferred ElutionRate: 0.0005-0.015 Micrograms/Hr

The drug core film was prepared using a solvent casting technique. 50 mgof latanoprost arginine salt and 200 mg of EVA-40 (Sigma ChemicalCompany, St. Louis, Mo.) were dissolved in 3 mL of dichloromethane(DCM). The polymer solution was cast on a custom-madepolydimethylsiloxane (PDMS) substrate, and the cast film was dried atambient temperature in a fume hood for 2 days. The drug core film with athickness of 90-100 micrometers was removed from the base and cut intodisc-shaped pieces with a diameter of 2 mm using a biopsy punch.

EVA-40 (Sigma Chemical Company, St. Louis, Mo.) was loaded into a filmmaker (International Crystal Laboratory) with a 50-micrometer spacer andheated to 75° C. for 4 minutes. The polymer was compressed at 300 psifor 1 minute and allowed to cool to room temperature. The polymermembrane with a thickness of 100 micrometers was removed from the baseand cut into oval-shaped membranes with an aspect ratio of 7.5 mm×3 mmusing a biopsy punch. This polymer membrane was permeable to water whenprepared in this manner. Some of these 7.5 mm×3 mm oval-shaped membraneswere subsequently manufactured to eye-shaped rings with a void of 2 mmat the center of the membrane. This polymer membrane is the “spacerring” (FIGS. 66-75). A 2-mm drug core film containing latanoprostarginine salt and EVA-40 was then inserted into the void of a spacerring, and both sides of the composite film were covered by a 7.5 mm×3 mmEVA-40 film (the permeable membrane). The four-piece assembly (2 EVA-40permeable membranes, 1 spacer ring, and 1 drug core film) was thenheat-sealed at 75° C. using a custom-made die set and allowed to cool toroom temperature.

In summary, this device was composed of a drug core film of 20%latanoprost arginine salt and 80% of EVA-40. The rate-limiting waterpermeable polymer was EVA-40, and the thickness of the water-permeablemembranes was 100 micrometers. The elution rate in this particulardesign was approximately 0.012 micrograms/hr.

Various features and advantages of the invention are set forth in thefollowing claims.

1. A device for insert in the eye, the device comprising: a firstportion including a recess configured to support a compositioncomprising an active agent, the first portion comprising an impermeablepolymer; and a second portion fused to the first portion, the secondportion comprising a rate-limiting water-permeable polymer that allowsfor transportation of the active agent to an exterior of the device.2.-4. (canceled)
 5. A device for insert in the eye, the devicecomprising: a non-bioabsorbable polymer structure comprising arate-limiting water-permeable polymer; and a composition supportedwithin an enclosure of the non-bioabsorbable polymer structure, thecomposition including an active agent; wherein the non-bioabsorbablepolymer structure includes a thickness in a range of about 200μιη toabout 800μιη, and wherein the thickness is configured to control anelution rate of the active agent through the rate-limitingwater-permeable polymer.
 6. The device set forth in claim 5, wherein therate-limiting water-permeable polymer is selected from the groupconsisting of: ethylene vinyl acetate with a vinyl acetate content ofabout 26% to about 80% by weight (EVA-26-80) and ethylene vinyl alcoholwith a vinyl alcohol content of about 40% to about 80% by weight(EVOH-40-80).
 7. The device set forth in claim 5, wherein therate-limiting water-permeable polymer is a copolymer having bothhydrophobic and hydrophilic monomers.
 8. The device set forth in claim5, wherein the active agent is selected from the group consisting of:3-hydroxy-2,2-bis(hydroxymethyl)propyl 7-((1R,2R,3R,5S)-2-((R)-3-(benzo[b]thiophen-2-yl)-3-hydroxypropyl)-3,5-dihydroxycyclopentyl)heptanoate(AR-102),7-((1R,2R,3R,5S)-2-((R)-3-(benzo[b]thiophen-2-yl)-3-hydroxypropyl)-3,5-dihydroxycyclopentyl)heptanoicacid (AR-102 free acid), dorzolamide, ethacrynic acid, latanoprost,latanoprost free acid, travoprost, travoprost free acid, bimatoprost,bimatoprost free acid, tafluprost, tafluprost free acid, dexamethasone,brimonidine, timolol, or salts thereof. 9.-10. (canceled)
 11. A methodof treating an ocular condition comprising implanting episclerally orsupraconjunctivally a drug delivery device comprising an active agent,wherein the active agent is released at a rate of about 0.0001 to about200 micrograms/hr.
 12. The method of claim 11, wherein the active agentis released at a rate of about 0.0001 to about 30 micrograms/hr.
 13. Themethod of claim 11, wherein the active agent is released at a rate ofabout 0.001 micrograms/hr to about 30 micrograms/hr.
 14. The method ofclaim 11, wherein the active agent is released at a rate of about 0.001micrograms/hr to about 10 micrograms/hr.
 15. The method of claim 11,wherein the active agent comprises a prostaglandin active agent, theactive agent being implanted episclerally and being released at a rateof about 0.00025 to about 0.0075 micrograms/hr.
 16. The method of claim15, wherein the active agent comprises latanoprost, travoprost,bimatoprost, each of their free acids or salts.
 17. The method of claim11, wherein the active agent comprises a prostaglandin active agent, theactive agent being implanted supraconjunctivally and being released at arate of about 0.0005 to about 0.015 micrograms/hr.
 18. The method ofclaim 17, wherein the active agent comprises latanoprost, travoprost,bimatoprost, each of their free acids or salts.
 19. The method of claim11, wherein the active agent comprises a rho-kinase active agent, theactive agent being implanted episclerally, and being released at a rateof about 0.02 to about 0.6 micrograms/hr.
 20. The method of claim 19,wherein the active agent comprises a Y-39983 salt.
 21. The method ofclaim 11, wherein the active agent comprises a rho-kinase active agent,the active agent being implanted supraconjunctivally and being releasedat a rate of about 0.04 to about 1.2 micrograms/hr.
 22. The method ofclaim 21, wherein the active agent comprises a Y-39983 salt.
 23. Themethod of claim 11, wherein the active agent is a non-prostaglandin andnon-rho-kinase active agent, the active agent being implantedepisclerally and being released at a rate of about 0.25 to about 7.5micrograms/hr.
 24. The method of claim 23, wherein the active agentcomprises timolol or a salt thereof.
 25. The method of claim 11, whereinthe active agent is a non-prostaglandin and non-rho-kinase active agent,the active agent being implanted supraconjunctivally and being releasedat a rate of about 0.5 to about 15 micrograms/hr.
 26. (canceled)